Week 8 Solution Mega Chemist Challenge #MegaCC

Sorry it is late………..

Well done this week to @AzaPrins who sent in the only correct answer.

Mega Chemist 8 was Ed Anderson who currently holds the position of lecturer at Jesus College, Oxford (UK).  Just to elaborate on the clues a little; on Anderson’s return to the UK from Sorenson’s group in 2003 he took up a Junior Research Fellowship at Homerton College, Cambridge (UK) working in the lab of Ian Paterson – beat that for a C.V. (don’t forget his DPhil with Prof. Andrew Holmes). In 2007 he moved to Oxford on an Advanced Research Fellowship, and became a lecturer at Jesus College in 2009.

Anderson made the Mega Chemist Challenge because I saw him speak a couple of years ago, and I loved his talk.  He was young, enthusiastic and inspiring. He also took a roasting from Professer Jim Thomas which he handled with great aplomb – this I regard as a great achievement because Prof. Thomas turns me into a gibbering wreck as soon as he looks at me. Although I have known this to be true for a long time, my second year viva really consolidated this for me!

Back to Anderson – His talk was amazing, great total synthesis (and methodology being developed out of it all over the place), so I was really excited about going back and devouring his latest conquest. Unfortunately though, there was nothing forthcoming, Anderson’s recent publications have all been methodolgy:

One-Step Preparation of Functionalized (E)-Vinylsilanes from Aldehydes
Org. Lett. 201113 (18), 4806.

Palladium-Catalyzed Asymmetric Synthesis of 2-Alkynyl Oxacycles
Angew. Chem. Int. Ed. 201150, 11506.

Palladium-Catalyzed Cascade Cyclization of Ynamides to Azabicycles
Chem. Eur. J. 201117, 14366-14370.

That is of course if you do not count the 2nd generation approach to Spirastrellolide A Methyl Ester, just out of the Paterson lab. Anderson’s name on this paper, I am sure is a result of his phenomenal lead work on the first generation synthesis from his time in Paterson’s lab rather than a recent contribution, so I am afraid in my mind this doesn’t count (also macrolides just don’t do it for me). Here is Totally Synthetic’s article on this work.

Instead I have gone digging into the past a little and pulled out the first (and still only) total synthesis of the furanosteroidal antibiotic viridin that Anderson completed in the USA. I had a browse through a few papers of Anderson’s, but this had not only an elegant alkyne cyclotrimerisation, but a “tandem conrotatory electrocyclic ring-opening 6pi-disrotatory electrocyclisation” – and you can not really turn one of those down!

Viridin is a potent anti-fungal that covalently inhibits protein function. Inhibition is reportedly through protein amine residues forming covalent bonds with viridin through reaction at the doubly activated carbon of the unusual electron deficient furan ring fused in the pentacyclic core. Anderson’s/Sorenson’s approach (scheme 1) took into account the sensitivity of this functionality, and as such intended to undertake the oxidative functionalisation of the A ring at a late stage. They intended to complete the pentacyclic core from napthelenofuran 2 which in turn would be generated through the key tandem electrocyclic ring opening-ring closing of a derivative of 3. The furan group was to be introduced through furanyl lithium addition to 4 which in turn would be generated from poly-alkyne in a rhodium catalysed cyclotrimerisation.

Skipping an unexciting beginning we arrive directly at cyclotrimerisation substrate 6 as an inconsequential mixture of diastereoisomers. Treatment of the triyne with [RhCl(PPh)3] (3 mol%) in ethanol gave 10 in an excellent 88% yield and in only 20 minutes (presumably excluding the column). Having generated the aromatic C ring, the cyclopentane moiety D and in the cyclobutanol a handle for generating the B ring in an impressive single step, Anderson et al introduced the furan ring through nucleophillic addition of 9 with complete anti-addition with respect to the vicinal methyl group, giving 8, and thus setting up the tandem electrocyclic ring opening-ring closing (scheme 2).

Taking us through the key reaction stepwise (scheme 3), we start with the conrotatory electrocyclic ring opening of 8 to give intermediate 10. The silyl group reportedly confers a high degree or torquoselectivity, ensuring that the furan rotates inwards setting up the 6pi electrocyclisation. Cyclisation proceeds to give 11 and subsequent in situ DDQ oxidation gives aromatised tetracycle 12 in impressive overall yield.

Think about how impressive this is – we have gone from the acyclic triyne to tetracycle 12 in only 5 steps in a 51% overall yield. Brilliant.

The final ring of viridin was installed in only three more steps. A one pot selective desilylation-allylation gave 13 which on heating in mesitylene installed the quaternary center of 14, and set up the ring closing metathesis needed to finish the core of viridin, giving 15 (scheme 4).

From 15 the end game is not that thrilling, though it does not detract from how much I like and am impressed by the synthesis up to here. This incredibly rapid construction of this pentacyclic steroidal core in only eight steps form 5 is wonderful.

To finish up from 15 (scheme 5), a SeO2 mediated allylic oxidation followed by a DMP oxidation-NaBH4 reduction installed the allylic hydroxyl with the correct stereochemistry, giving 16. This allowed for a ‘Donohoe’ hydroxy-directed dihydroxylation giving 17, with all the stereocenters installed.  Protecting group manipulaion and oxidation took it the rest of the way through to viridin in an overall yield of 5.0% from pent-4-yn-1-ol. Fantastic.


Week 3 Solution Mega Chemist Challenge #MegaCC

The first postcard out of the bag this week with the correct solution – Sarah Reisman – was from Tynchtyk.  Congratulations.

As Reisman is new to the game as it were, I have already dished out all of the biographical details I could find in the clues so we will get straight into the chemistry.

The selection of last weeks Mega Chemist, the one and only Sarah Reisman of Caltech was in fact a little self serving.  Obviously I really enjoy Reisman’s impressive total syntheses (otherwise selection for #MegaCC would obviously not have been so rapid) one of which is up for discussion today, but excitingly she has utilised my favourite reaction developed in the Procter group whilst I have been here; a SmI2 mediated reductive dialdehyde cyclisation cascade. Thus, here is my first opportunity to exalt the virtues of the sometimes derided SmI2 – the bread and butter of the Procter group.

The Reisman paper in question is the first total synthesis of (-)-maoecrystal Z published last year in JACS, and hot on the heels of the long sought after (-)-maoecrystal V which was finally pinned down by Yang the year before. 

Now for me personally,  natural products like maoecrystal Z bring me out in cold sweats when planning a synthesis; the general lack of functionality and the complex tetracyclic core with six contiguous chiral centers should prove a nightmare for most. Reisman though, appears not even a little afraid; a clever retrosynthesis and the impressive 12 step synthesis that realised maoecrystal Z show both her ambition and ability.

Diving straight into the key step of the retrosynthesis Reisman planned to utilise a SmI2 mediated dialdehyde cyclisation cascade (scheme 1) developed in the Procter group. You can see the development of this reaction here and here, though more excitingly you can see the first full application in an effective formal synthesis of pleuromutilin utilising SmI2 with tBuOH as a co-solvent.

Reisman proposed that the single electron reduction of the presumedly ‘more kinetically accessible aldehyde’, would generate a ketyl radical that would undergo intramolecular addition to the unsaturated lactone (pink line).  A second electron transfer would subsequently generate a samarium enolate of the lactone which would undergo aldol cyclisation with the waiting aldehyde (blue line), generating the tetracylic core of maeocrystal. Reisman’s kinetic arguments for the selectivity of the reduction are solid, though it should also be considered that the single electron reduction of aldehydes may be reversible, and that the ability of the ‘less hindered’ aldehyde and hence its ketyl radical to undergo a facile 5-exo-trig cyclisation vs. a possible 4-exo-trig cyclisation for the alternate aldehyde may account in part, for the chemo-selectivity of the reaction.

Reisman’s awareness that the diastereocontrol may be difficult to predict led to an initial study on the 5-exo-trig radical cyclisation. The substrate was elegantly prepared from epoxidised gamma-cyclogeraniol using a modification of Gansauer’s modified conditions for intramolecular Ti (III) mediated couplings of epoxides and acrylic acids (scheme 2) generating spirocycle 1 as a single diastereoisomer in excellent yield.

Alkylation of 1 and a little more fiddling around gave 2 which allowed the radical cyclisation to be studied (scheme 3).

Initial cyclisation attempts using solely SmI2 in THF resulted in decomposition of the starting material but a screening of additives found that a SmI2-tBuOH-LiCl reagent system did the trick (we will come back to that later), giving the proposed product in respectable yield.   Reisman cites the shown steric interactions for obtaining the correct stereochemistry (scheme 4).

With the first cyclisation looking good, they went for gold.  Exchanging LiCl for LiBr  they realised the target compound,  generating both rings and four contiguous chiral centers in one pop, in an impressive in 54% overall yield (scheme 5).

With the key step nailed, as all of us who have worked in total synthesis know you are home and dr…….. or, back in the real world, your apparently simple protecting group chemistry to finish up proves formidable; and this was the case for Reisman.  Happily though Reisman circumnavigated  these issues and did get to maeocrystal Z in just four additional steps. An excellent total synthesis.

For me the most intriguing aspect of this synthesis (particularly as a Sm chemist) is the additives used in the cyclisation.  It is well know that you can modulate the reactivity and often the selectivity of SmI2 using a host of additives including Lewis bases such as HMPA, DMPU; proton sources including but not exclusively H2O, MeOH, tBuOH; and metals and their salts, including LiCl and LiBr as demonstrated by Reisman.

In principle Reisman’s cyclisation  simply requires the formation of a ketyl radical from an aldehyde which is easily achieved with SmI2 alone, though it was reported this led to degradation of the starting material – maybe due to reduction of the aldehyde (s) without cyclisation, or a selection of pinacol type products.  She found, as was the case in the pleuromutilin synthesis that the addition of tBuOH facilitated reaction, though its role is somewhat unclear.

tBuOH is known to increase the reductive potential of SmI2 – pep it up a little if you like – though in principle this should not be required.  The ‘other’ role tBuOH can play is as a proton source, though in my mind this can only be a bad thing; as we increase the number of protons floating around we risk protonating the enolate generated after the radical cyclisation, preventing the aldol reaction to form the second ring! This is an intriguing conundrum, with still no light to shine on it!

In addition to tBuOH Reisman also used LiCl or LiBr in her cyclisations, both of which are know to give SmI2 even more get up and go. The fact that these are required at all, never mind that they don’t lead to all sorts of side reactions is a mystery to me. Another conundrum still to be solved; though I do wonder what happened to the other 46% of starting material.

So despite SmI2 sometimes getting a bit of negative press, especially from industrial folk (and no, Sm is not radioactive) I think I have shown here its potential in total synthesis – 2 rings, 4 steroecenters in both maeocrystal Z and pleuromutilin in a SINGLE step.

The applications of SmI2 in functional group transformations and radical and anionic bond forming processes are massive, and the control and selectivity often achieved with the addition of additives is very impressive.  You can find more information online – though I feel I have to mention this beautiful book to maintain favour with my boss.

And keep an eye out on Nature’s protocol exchange, an idiots guide to preparing SmI2 will be coming your way soon.

Week 3 Clues Mega Chemist Challenge #MegaCC

So we already have a winner, but if you avoid the comments section you can still try and guess who this weeks rising star is.  Being a rising star, biographical information is rather limited, but if you know your total syntheses better than faces this should be no problem.

I obtained my PhD in 2006 at Yale University under the supervision of Prof. John Wood publishing three papers on approaches to, and the total synthesis of welwitindolinone A isonitrile – with a combined total of 142 citations to date. I moved as an NIH fellow to the group of Prof. Eric Jacobsen at Harvard before taking up my current position as an assistant professor.  Since commencing my independent research career  I have completed a number of total syntheses including the first total synthesis of (–)-maoecrystal Z, and more recently that of (-)-acetylaranotin.

Answers on a postcard.

Week one solution for the Mega Chemist Challenge

Well done to Shaun Pollock and Richard Collins, the solution is indeed Kurt Alder. Alder is arguably one of the most famous synthetic organic chemists of all time owing to the reaction developed alongside his mentor and PhD supervisor Otto Diels. The Diels-Alder [4+2] cycloaddition (or diene reaction) is known by all who have studied organic chemistry, and becomes beloved by those with a penchant for total synthesis (in particular one Professor Samuel Danishefsky). Alder is also know for his extensive studies and development of the hydro-allyl addition or Alder (ene) reaction.

Here I have linked to some of the seminal work of Alder in both the Diels-Alder and the Alder-ene reaction, though unfortunately these are all written in German and currently my translation skills on a scale of 1-10 come in around 0. Should anyone be aware of translations online or be capable and willing to undertake such a challenge themselves I would love to hear from you.

Cause of the “azo ester” reaction

Addition of “diene” hydrocarbons

Addition of azodicarboxylic esters to aldehydes 

Substitution processes in the allyl position

A full biography of Alder can be found here via nobelprize.org

Finally, I want to try to finish each solution to the Mega Chemist Challenge with some relevant chemistry that I love (or at least have read in my own exploration of the author).  For week one I can not help but talk about Corey’s beautiful  use of the Diels-Alder reaction in his 1969 synthesis of prostaglandins F2α and E2.  Those of you whom have read this before can once again revel in its magnificence and the warm feeling of inspiration that it imbibes into you; and those of you fortunate to read it for the first time, read it again and take note!

My fascination with Corey’s prostaglandin synthesis is that on not only the first, but for a considerable number of glances after, a Diels-Alder disconnection is not apparent. We have a fully saturated five membered ring and two double bonds which scream Wittig/HWE type disconnections, but not a six membered ring in sight, nor a reconnection to form one.

Taking extreme liberties and stepping into the mind of the forefather of retrosynthesis, I hypothesise that after the obvious double bond disconnections Corey arrived somewhere in the region of 1, with the three contiguous chiral centres installed (scheme 1). Even here though, it still takes beautiful vision to see that these three centres can be installed in a single step using a Diels-Alder reaction.

Corey skillfully envisioned the cycloaddition of 5-methoxymethyl-1,3-cyclopentadiene and 2-chloro-acrylonitrile to give a mixture of bridged bicycles which were readily converted into a single product 2 with the three stereocenters installed.  Subsequent Bayer-Villager oxidation, followed by saponification and in situ iodo-lactonisation to give 3, all proceed exceedingly well and without contemporary purification techniques (scheme 2).

As a (young) synthetic chemist this paper impresses not only with respect to the chemistry, but what can be achieved with what many may now regard as frightful working conditions; we should all take note and maybe not reach for the columns so readily. Lines must be drawn though, and should I be informed that I was only allowed a 60Hz NMR spectrometer for the rest of the week, I must be honest, I would probably just go for a pint and not come back!

p.s. Any advice on making ChemDraw look good on WordPress would be very welcome.