Baran, Burns, Krylova, Hannoush. JACS, 2009, ASAP. DOI: 10.1021/ja903745s.

Oh, we’re going way back here… a whole three weeks before I started blogging!  This brings us all the way back to Baran’s first conquest of haouamine A (and his eleventh paper), racemic, and in this JACS. It was followed up by an Angewandte two years later, but I’ve apparently only covered Weinreb’s synthesis, also back in 2006.  Part of the reason for all this interest is that the molecule seems to exhibit an unusual isomerism.  Baran realised after his initial work that thee were two isomers of the target, configurationally identical, and sharing the same stereochemistry about the 6,5-ring junction.  This meant that the stereochemical divergence must be unusual - with two candidates - atropisomerism of the bent phenol or slow pyramidal inversion at the THP nitrogen.  The only way to probe this effectively was to attempt a synthesis of the two atropisomers, and compare with the isolate.

The synthesis, yet again, is racemic, and proceeds from an intermediate in their first synthesis.  As I didn’t cover that paper, I’ll describe it’s synthesis firstly to make the route more transparent, and secondly ’cause it’s pretty sweet.  The SM was produced very quickly, using a standard enolisation and trapping with an alkylating agent to generate the quaternary center.  The ketone used was then hydroxylamine-d, and treated with a source of electrophilic bromine, causing a 5-exo-trig cyclisation and formation of a nitrone.  Reduction of the nitrone produced the intermediate I’ve shown, which after tickling with a bunsen gave an aziridine.  Rearrangement of this allowed ring-expansion to give a tetrahydropyridine-N-oxide, reduced with a bit of indium.  Nice work!

A simple (but well executed) Suzuki coupling allowed completion of the macrocyclisation precursor (and an Appel reaction too…), which was simply de-Boc-ed and treated with base to prompt alkylative cyclisation in a pretty decent yield.  Interestingly, a stereochemical bias was found where none would be expect - even if slight.

The key reaction was the oxidation of this cyclohexenone to a fully-aromatic system - a reaction with a wealth of possible reagents.  However, some of the more obvious choices, such as manganese dioxide or palladium prove ineffective, so they leapt on a Mukaiyama protocol.  Initial developed to introduce ?,?-unsaturation to ketones, this one-pot procedure did a pretty decent job of oxidising the chiral cyclohexenone to a planar-chiral phenol, returning a respectable mass-balance.

A few more steps were requred to complete the targets, which Baran mentions was also done with enantiomerically pure material (perhaps after doing a bit of semi-prep chiral HPLC).  This gave them both atrop-isomers, a few crystal structures, and an opportunity to biologically profile both.  As it turns out, their IC₅₀s were with in analytical error…

Snyder, Tang, Gupta. JACS, 2009, 131, 5744. DOI: 10.1021/ja9014716.

Okay, it’s taken me far too long to get around to this article - I actually wrote the Chemdraw back when this article was in ASAP… but other stuff got in the way, like a little Nature paper from Baran.  However, it’s a damned nice paper, so it’s impossible for me not to go back and look at it properly.  The target here is an halogenated natural product, isolated from Streptomyces bacteria - so it’s not too surprising that this family possess antibacterial activity.  The headline, though, is in vivo activity against MRSA and VRSA strains - a guaranteed grant-winner!  This brought quite a bit of attention, and a racemic synthesis by Tatsuta back in 2002.  However, Snyder has set his sights a little higher, with an enantioselective synthesis in this paper.

The starting point for this post is a bit of chemistry on flaviolin; a prep published when flash chromatography was but a dream… This prep took eight steps to complete flaviolin, but Snyder managed to shorten it to only two - neat work.  The first step I’m covering, and keeping the chemistry nice and flat, is a  Knovenagel condensation (bear in mind the 1,3-diketone tautomer), followed by a sigmatropic electrocyclic rearrangement to give the the desired tricycle.

Now it was time to get asymmetric, doing a dichlorination using a bit of Lewis acid, chlorine gas (eeeeh…), and some BINOL-type axially-chiral ligand.  The prep for this is quite interesting, as they had to use four equivalents of the BINOL-thing, stew it up with borane-THF and isolate the intermediate, which is presumably the chiral-borane adduct. Addition of the substrate at this point, and chelation of the borane is controlled by pi-stacking interaction, and allows selective trans- delivery of chlorine across the double bond.  Neat, but that’s a lot of 9 in the pot - a point addressed by Snyder, who stated that firstly that the ligand could be recovered, and the excess was required to prevent chlorination of the aryl moieties.

They then selectively functionalised the allylic chloride by displacing with acetate, and with retention of stereochemistry by using potassium acetate and 18-c-6, which presumably presents a source of naked acetate.  The acetate group was removed to free the hydroxyl, and the remaining phenol protected - setting them up for a Tot.Syn. favourite - a Johnson Claisen.  This bad-boy does a fantastic job of rearranging the allylic alcohol into a hetero-quaternary center, and providing a methyl ester as a functional handle.  The yield of product was unfortunately low, but if you consider the congested transition state here, it’s not too surprising; at least they were able to recover the SM.

I’ll stop about here, as completion of the target didn’t take much more effort.  The ester was reduced and Wittiged, whilst the final stereocenter was imparted using base and NCS.  Unfortunately this resulted in the enantiomer of the target, but that doesn’t matter a damn.  Good stuff!

Barbas, Bui, Syed. JACS, 2009, ASAP. DOI: 10.1021/ja903520c.

Now, this is a bit of a fib already. I’m not entirely sure of Barbas’ reason for calling this paper a ‘formal total-synthesis of physostigimine’, as, whilst it is a formal synthesis, he actually stops at another natural product, esermethole.  Now, this is fine - and it’s still a formal synthesis of physostigimine, but it is moreso a total synthesis of esermethole.  Why he felt the need to call this a formal synthesis I don’t know.

It’s a shame to dwell on this, though, as the synthesis is pretty sweet.  Starting with a lightly-functionalised indolinone, he is able to demonstrate a pretty wide variety of Michael additions to nitro-olefins.  Not only were these reactions highly enantioselective, he was also able to demonstrate good diastereoselectivity in the case of non-terminal nitro-olefins.  This was done in conjuction with a fair-old catalyst screen, turning up Takamoto’s thiourea catalyst as the winner.  Other thiourea-based catalysts were also active, but the difference between >90% e.e. and <10% e.e. was remarkable WRT catalyst design.

So with the addition done, and a quaternary center in place, completion of the synthesis only took a few more steps. Reduction and ‘protection’ of the nitro group allowed a reductive cyclisation to to complete the cis-ring junction, with somewhat unsurprising diastereoselectivity (making the trans- fused analogues is tough).  This completes esermethole, with a reference to Overman’s work converging the syntheses.  All that’s required is a deprotection followed by addition into an isocyanate to give the carbamate - so no real sweat (though it’s worth examing Overman’s yield-issues in the original paper…).

Interestingly, this a similar piece of work turned up in Chemistry - A European Journal this week too…

Nakamura, Hara, Shibata, Takeshi. Chem. Eur. J, 2009, EarlyView. DOI: 10.1002/chem.200900944.

So the compound we’re making here is distinctly less complex, using a different approach to create a similar benzylic stereocenter (an aldol in this case).  There’s even a similarity to the catalysts used in each synthesis.  The limitation here is the scope of the paper (which is only a Chem. Eur. J. communication) - the addition chemistry is only demonstrated using acetaldehyde, something the authors seem quite happy about.

It’s be interesting to see how both of these reactions are adopted over the coming years.  Nice work all around.

Latest piece for the RSC in the June issue of Chemistry World, making a rather popular molecule [1, 2].

List, Michrowska. Nature Chem., 2009, AOP. DOI: 10.1038/nchem.215.

Another rather short blog post, but why wax-lyrical when the synthesis is short and sweet?  Ben List is still hammering-away at his niche in organocatalysis, this time reporting a rather nice domino reaction.  The target of the synthesis is a isolate of a liverwort, and possesses “potent molluscicidal activity” - not a biological effect I’d come across before.  It turns out that this natural product spells doom for Biomphalaria glabrata water snails…  and we’re still at a loss.  Water snails irritate me too, especially when having a bath, but the plot thickens… it turns out these slimy little devils vector schistosomiasis, a nasty tropical disease - bad news.  So it’s worth working on a treatment for the cause, rather than the symptoms.

Several syntheses have been published in the past - one that I can’t see online by Takeda (Heterocycles, 47, 1, 277-282), one by Liu (10.1021/ol052638r), and another by Audran (10.1055/s-2005-871932).  As short as some of those are, this is something special.  A (mostly) linear precursor was built quickly using an dehydrative aldol, followed by a bit of cross-metathesis.  Initially, they used Grubbs G2, but found that the addition of a nitro group put oats in the fodder-bad, and drop the loading whilst increasing the yield.  And it’s probably not patented.

With the precursor complete, List did what he does best - a bit of organocatalysis - resulting in a reductive Michael addition, which produced a cyclohexanal intermediate.  The yield was great, but the diastereoselectivity was a nightmare - 2:1, and in wrong direction (if you like).  However, the enantioselectivity was very good, so the group hoped that they might be able to improve the situation.  It turned out that dumping in the reagent for the Tishchenko reduction (a bit of samarium triisopropoxide) had a pretty impressive effect - epimerisation of the errant stereocenter, and then reduction to give the desired diastereoisomer, and the product, in a very healthy yield.  List explains this complete diastereoselectivity by invoking chelation of the catalyst by both carbonyls, which leads to the product.

Damn nice work!

van Maarseveen, Hiemstra, Wanner, Boots, Eradus and de Gelder. Org. Lett., 2009, ASAP. DOI: 10.1021/ol900888e.

Okay, jsut a little Org. Lett. to get my hand back into this blogging thing after being on holiday for a week.  The writing conditions have changed a little in Tot Syn towers, too - I’m now typing this on a new keyboard - a lovely aluminium Apple thing.  So I bid my old Microsoft ‘Natural’ keyboard goodbye, after six years of faithful service, and also six years of crud (putting it as delicately as possible) under the keys.  And a thesis too.  So this is the first real test for the new ‘board, so lets see how it does.

This paper from Holland is definitely a methodology paper with a bit of total-synthesis to prove the point… and looking back into the past, the methodology was proved last year.  The key is an organocatalytic asymmetric Pictet?Spengler reaction - a useful approach, and one that has been developed by other groups (see reference two).  Using an elaborated BINOL-phosphoric acid catalyst, in rather low loading, they were able to develop a rather useful yield and enantiomeric excess.  By reducing the planiarity of the naphthalene moieties, the e.e. could be further enhanced, with the price being a more exotic catalyst.  I’m not entirely sure which one they ran with, but I’m fairly sure it was catalyst B, as they were able to run the reaction on a 5 mmol scale.

With the vast majority of the compound complete, they group were left with only one more C-C bond forming reaction to complete.  This vinyl iodide-enolate coupling was lifted from some work by Sole and Bonjoch back in 2004 (it’s in Adv. Synth. Catal. - not a journal I read enough… never enough time!), and works reasonably well in this case.  This is a situation where, whilst the yield was moderate, the result meant that they had their synthesis complete in only five steps (from known precursors).¹ With only a deprotection remaining, this is a good job well done - proving the utility of their method nicely.  I look forward to seeing it used by other groups in the near future!

[1] Why am I bothered about this?  Well, one of the tendancies I see more often these days (probably cause I’m looking for it) is for PIs to only publish in JACS or ACIEE (or better), meaning that only the best chemistry gets published.  This means that the (mearly) very good chemistry (you know what I mean - 80ish% yields, or 4:1 d.r., et c.) gets left on the bench, and no-one wins.  Grrr.  Any contrary views?  (Sure, I know it’s nice for PIs to have that lovely list of publications, where it’s only those top-rung journals.  But surely there’s space for other journals in there…)

Davies, Williams, Schwartz, Denton, Lian. JACS, 2009, ASAP. DOI: 10.1021/ja9019484.

Now that’s a substituted ring…  done and dusted by Huw Davies and Craig Williams as a collaborative effort (I’d quite like to know how this worked, as the two groups are quite removed), with Davies weighing in with some smart chemistry for building seven-membered rings.  This clearly critical to the synthesis of such a molecule, but the challenge is the heavy substitution, which has thwarted several groups (including individual efforts).  Whilst this paper doesn’t complete the parent molecule, vibsanin E, the C-5 epimer is also a natural product, so they get the badge for this impressive work.

It’s that neat cycloheptadiene-forming chemistry that kicks this synthesis off, using a vinyldiazoester and a triene (derived from Geraniol) to form a cyclopropane.  This was done enantio- and diastereoselectivly using Davies rhodium chemistry, and a catalyst containing a very bulky ligand (that Ad is adamantyl).  However, diasteroselectivity was unnecessary, as that cyclopropane snapped-open in a [4+3] to generate the requred seven-ring, and a quaternary centre in cracking e.e. and decent yield.  Considering the complexity of the system, that’s quite a success - but it took a bit of optimisation, which I’ll leave in the paper.

With one ring firmly in-place, the next two followed very quickly by completing a Lewis-acid promoted hetero-Diels-Alder.  One new stereocenter followed, along with both rings, in excellent yield.  Things started to get a bit more difficult here, as functionalising the ring isn’t particularly easy.  Medium rings, like this bad-boy, often have unique conformations, which can play-havoc with stereoselective reactions.  Davies and Williams approach was use a Claisen rearrangement to impart one of the more tricky stereocenters, but this was problematic, as they first had to generate an enolate with the correct regiochemistry.  Silylation, followed by allylation of the ketone (developing the correct regiochemistry) was quite effective though, and microwave assisted rearrangement gave the desired product in a reasonable yield and decent d.r. (again, considering the system).

Completion of the synthesis required only a few more steps - deprotection, oxidation and olefination of the primary hydroxyl using Williams chemistry (an Anders–Gaßner modification).  Although this olefination doesn’t look particularly traumatic, the trans-vinylacetate moiety seems to be particularly difficult to install.

This is a nice piece of work, showcasing work gleened from both groups, making a pretty recalcitrant molecule.

Baran, Chen. Nature, 2009, AOP. DOI: 10.1038/nature08043.

They say that the best defence is a good offence, so I’m going to start latterly - and remind (somewhat forcefully, if necessary) all prospective commenters that the folks at Nature decreed that this paper is worthy.  That’s good enough for me, so let’s avoid the tired arguments about suitability… </pre-emptive rant>

Anyway, what we’ve got here is typical of Baran - re-examination of chemical methodology of the past, and modernisation to solve problems in an orthogonal fashion.  Breaking that down, what he seems to be really good at is picking up an idea from the past, re-examining the goals, and using modern techniques and reagents to solve problems.  This appoach often allows him to disregard common retrosynthetic failings, such as recursive oxidation / reduction and protecting group abuse - but must come unstuck quite often.  (I don’t know that it does come unstuck, but I rather hope that is the case for my own sanity…)  Today’s target are terpenes, and the old-school technique I alluded to is remote oxidation.  This one generally describes selective (and unactivated) C-H oxidation using a scaffold in which a remote group provides the impetus/selectivity.

Of course, the first requirement is a skeleton to work with, and rather than a semi-synthetic intermediate, Baran decided to make his own (and rather quickly too).  First up is a little organocatalysis, using a standard proline-based catalyst to do an enantioselective Michael addition, which following a spot of base give the cyclohexenone in great e.e. and decent yield.  Notable is the low catalyst loading (5% is pretty good for organocatalysis), and the use of a catechol to activate the enone for addition.

A few steps further on, and they’d bolted another ring to the cyclohexenone, with a cross-conjugated diene and single stereocenter in place.  However, three simple reaction allowed the group to greatly enhance the stereo-complexity - cuperate addition and a pair of reductions - and now we have five stereocenters.  Nice work!  This trans-decalin is the least-oxidised (most reduced) carbon skeleton from which Baran works, and it’s a good thing he has such a concise route towards it, as he targets several natural products from here.

All of these targets share one further oxidation, so it makes sense to put it in first.  This is done by firstly appending a controlling group for the remote oxidation - a carbamate featuring a trifluroethyl chain.  This choice was directed by their methodology for 1,3-oxidation published last year in JACS, and is related to the Hofmann-Loffler-Freytag reaction (used to do a 1,3-bromination via atom transfer).  Their development of this chemistry lead to the use of a trifluroethyl group to encourage N-centered radical formation, increasing selectivity.  So we’re all-set to do a bit of 1,3-oxidation, but there’s a complication - as there are three possible tertiary centers avaliable.  Their smart move was a bit of rationalisation using 13-C NMR to probe the electronegativity of the various carbons, confirming that they had a good chance of selectivity, which was bourne out.  In this case, it works really quite well, using methyl(trifluoromethyl)dioxirane - a varient of DMDO in which is more active, and selective for equitorial C-H bonds.

The next most reactive position for this chemistry was dealt with accordingly, but this time doing a bromination to provide a common intermediate, 18.  In the simplest case, treatment with silver carbonate resulted in the diol, which after clevage gave pygmol in cracking yield over four steps.  It’d be interesting (but a lot of work) to see if this could’ve been stereoselecive, had the center been prochiral.

Using the same intermediate, Baran was able to complete two more targets, 11-epieudesmantetraol and eudesmantetraol, by firstly eliminating the bromide with tetra-methyl piperidine (can I assume that the methyl groups are bis-geminal, alpha to the nitrogen?), and then brominating with NBS to form a cyclic carbonate.  This time we’re stereoselecitive, and it remained so when the opened the carbonate, which closed onto the primary bromide to give a terminal epoxide.  Only one step was required to access each natural product, choosing either acidic or basic condition to open the epoxide (remember your first-year org-chem?).

This is a fantastic piece of work - not just smart, but well executed.  However, it’s worth remembering that this approach isn’t entirely new, as remote oxidation was a very popular technique for steroid chemists.  Use of transition-metal oxidants, such as iron coordination complexes was common, such as in this example by Paul Grieco.  However, Baran had taken this idea and modernised it considerably, with the NMR/X-ray analysis of reactivity a critical step.

Apparently, they want to blacklist researchers who apply for funding but are unsuccessful in their application in more than 75% of cases.  Most academics get the odd proposal refused, so the average failure rate is 65-85% - meaning many would be black listed.  Please consider signing the petition (created by Prof. Joe Sweeny):

http://petitions.number10.gov.uk/UKScience/

This proposal can only hurt younger and less well established academics, ruining their progression and careers.

Thanks! (Especially to Martyn for alerting me of this)

Lee, Jung. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200900865.

Another month, another amphidinolide - but we’re getting pretty close to the end of the alphabet now.  Actually, I’m (as ever) being rather over-the-top - we’ve not actually covered that many, but X & Y (as well as being an affront to my ears) were blogged in 2006, where the focus was on the THF synthesis.  This is the case again with Eun Lee’s synthesis, which almost disregards the polyketide-style sections.

The key to his synthesis of the THF is a bit of new methodology, capable of creating two new stereocenters in the process.  The key elements are the two existing stereocenters, and the olefin - which combine to impart asymmetric control.  The actual degree of control stemming from these elements is considered thoroughly in the paper, with a large array of possible substrate chucked into the radical pot.  The 5-exo radical cyclisation seems to be stereospecific, and to quote Lee, ‘the structures of the major products may be predicted on the basis of the double-bond stereochemistry and the sulfoxide configuration.’  As there are two control elements, there are a pair of matched and unmatched possibilities, with the distereomeric ration ranging from 15:1 to 3:1 depending on the case.  Interestingly, the reactions of the less-substituted secondary alcohol starting materials is stereochemically unrelated…

After an interesting protection (using a p-nitro benzyl group), it was time to remove the ‘auxilliary’, and this is perhaps where the methodology wins it’s ‘keeper’ status.  A simple treatment with TFAA and a bit of base resulted in a Pummerer rearrangement, and generation of the aldehyde in cracking yield - a nice result.  Going back to the chiral sulfoxide used in this chemistry, it should actually be fairly easy to make using Kagan’s approach.  This uses almost identical conditions to the Sharpless asymmetric epoxidation to allow asymmetric oxidation of a sulfide, and normally works really well if the two sides of the prochiral sulfide are sufficiently differentiated (as in the CBS reduction).

As I said in the intro, Lee doesn’t exactly wax lyrical about the rest of the synthesis, aware that the fragments required for the rest of the macrocycle are well documented.  That leaves us with the strategy for coupling, which works well for them, starting with a pair of olefinations to homologate the aldehyde, and then metathesis to bolt-on the rest of the top.  A pair of esterifications (using acid-chloride chemistry) builds up the bottom-half, with RCM to complete the ring.

This paper isn’t really about the total-synthesis, but the methodology, and it’s pretty neat; the succinctness of the rest of the synthesis is testament to Lee’s retrosynthetic skill.