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123713AB lecture06


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The big topic of the last few years, the use of small organic molecules to catalyse enantioselective transformations. This lecture will start with proline before moving on to some of MacMillan's contributions to this field and, finally, finish with hydrogen bond catalysts and Brønsted acids.

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123713AB lecture06

  1. 1. The last of the lectures devoted to asymmetric synthesis will look at organocatalysis. This was the big growth area in asymmetric catalysis over the last 10 years but has now settle down to be another valuable tool in the synthetic chemists arsenal ... There have been a number of different ‘sales pitches’ for organocatalysis but I believe there are three benefits arising from organocatalysis: 1) the catalyst are robust (unlike many metal complexes) 2) new/unorthodox transformations have become viable 3) cleaner chemistry 1
  2. 2. ... to become more environmentally benign chemists must think about how we do chemistry. The big problems are: • solvents • purification • atom economy Organocatalysis is just another (useful) tool to address these problems. By cleaner the normal ‘sales pitch’ is that organocatalysis avoids the use of toxic and expensive metals that need to be removed from the reaction mixture at the end of the process. This is only half the story ... 2
  3. 3. Nature has understood the principle of organocatalysis for a long time. Many enzymes do not require the presence of a metal to catalyse reactions ... ... for example certain aldolases use enamine (condensation of an amine and carbonyl followed by tautomerisation) chemistry to catalyse the aldol reaction. Taking this (and other reactions) as inspiration, organic chemists have developed a toolbox of simple organic molecules that can catalyse a host of different transformations. 3
  4. 4. There have been many monographs written about organocatalysis and I thoroughly recommend you read some. Good starting points are:! divAbstract! divAbstract The reaction the probably kickstarted the organocatalysis field was the proline- catalysed aldol reaction. Here the simple amino acid catalyses the direct aldol reaction of non-activated aldehydes (unlike the Mukaiyama aldol reaction we saw earlier that requires formation of the silyl ketene acetal). As you can see the reaction is highly diastereo- and enantioselective. 4
  5. 5. O H N O H H O H There is debate as to the transition state for the proline catalysed aldol reaction but this simplified mechanism will do for now ... The first step is condensation of the proline with the less sterically demanding aldehyde. This initially gives the iminium ion. ‘Tautomerisation’ generates the nucleophilic enamine. Addition to the aldehyde reforms the iminium cation. Hydrolysis regenerates the catalyst and releases the product. The transition state is probably similar to the one shown above, with a proton tethering and activating the incoming aldehyde. It is possible that the proton is also interacting with the lone pair of the nitrogen to give a more rigid structure. This is a little bit stylised to allow the transition state to be drawn based on the chair but is close to the predicted structure (and highlights the value of being able to draw that 6-membered ring). 5
  6. 6. The proline-catalysed direct aldol reaction effectively started what has been termed the organocatalyst ‘gold rush’. Literally hundreds, if not thousands, of papers using various amines to catalyse a host of reactions. Some of those papers are excellent but there is a bit of ‘bandwagon’ jumping going on as well so you will need to filter the papers ... Here are some examples of the power of this reaction manifold and the classic catalyst structures ... A number of attempts have been made to improve the structure of the catalyst (proline is not soluble in many organic solvents). Prolinol derivatives have a wide variety of uses. Here is an α-fluorination. The aldehyde is reduced before isolation to prevent racemisation of the highly acidic α-position. 6
  7. 7. The mechanism is very similar to before; amine condensation to give the iminium species. Deprotonation gives the enamine. Nucleophilic attack on the source of “F+” gives the iminium species, which is hydrolysed to product and catalyst. The silyl protecting group prevents formation of a non-active hemiaminal. One of the most successful classes of organocatalyst is the imidazolidinones introduced by MacMillan. 7
  8. 8. These are readily prepared from amino acids thus allowing easy access to a structurally diverse array of chiral molecules. Condensation to form the aminal means more sterics or functionality can be readily incorporated into the molecule. The imidazolidinones promote enamine- based reactions like proline and prolinol derivatives. The mechanism is just the same; condensation, deprotonation, nucleophilic attack and hydrolysis ... 8
  9. 9. Just as an example ... here a phenylalanine and acetone derivative is used in an α- chlorination reaction. Hopefully you can see that the reagent in red is a good source of “Cl+” as this would result in the formation of an aromatic by- product. And now for an example of the MacMillan chemistry being employed in the synthesis of a natural product ... 9
  10. 10. First the hydroxyl stereocentre marked in red was introduced by a proline-mediated α-hydroxylation reaction. This follows the standard enamine mechanism. There is some debate as to the nature of the transition state. It could be identical to the aldol reaction earlier or might occur through a more pronounced 6- membered ring with all the major substituents trying to adopt the pseudo- equatorial conformation. An aldol dimerisation catalysed by proline installs two of the stereocentres found in the carbohydrate moiety. The mechanism and transition state were given earlier. 10
  11. 11. This example is taken from the synthesis of a potential pharmaceutical compound ... It involves the conjugate addition of an enamine to a nitroalkene. The catalyst is a proline derivative in which the carboxylic acid functionality has been replaced with a highly acidic sulfonamide fragment. As you can see the reaction is highly effective with good yields, diastereo- and enantioselectivity. 11
  12. 12. The transition state is believed to be more complex than those we have looked at before and might involve water/solvation as means of organising the two substrates. Organocatalysis takes many different forms and is not just about the formation of nucleophilic enamines. An incredibly powerful form of organocatalysis is the use of iminium species to replace Lewis acid catalysis. Lewis acid catalysis normally involves the lowering of the Lowest Unoccupied Molecular Orbital (coordination increases the polarisation of the molecule by dragging electrons towards the Lewis acid). 12
  13. 13. This can be achieved through the formation of an iminium ion. The charged intermediate activates the double bond to nucleophilic attack or cycloaddition with the electron rich molecules such as dienes ... ... here is an example of a secondary amine promoting the conjugate (1,4- or Michael) addition of a malonate to an enone. This elegant example of ‘green’ chemistry (no solvent, good atom economy) proceeds with good yield and excellent enantioselectivity. 13
  14. 14. The reaction proceeds through the standard formation of the iminium species. In this case deprotonation to give the enamine is slower than nucleophilic attack. The geometry of the iminium species is thought to arise as a result of π-π interactions (π stacking). This blocks approach of the malonate from the top (Re) face so it must approach from the bottom (Si) face. This chemistry has been used in the synthesis of warfarin, a blood thinner ... 14
  15. 15. ... as well as a rat poison ... In this reaction the secondary amine activates the enone, making it more electrophilic while creating a well-defined chiral environment. The nucleophile (tautomeric form of a β-ketoester) then attacks from the least sterically demanding face of the iminium species. Hydrolysis regenerates the catalyst and frees the product. 15
  16. 16. Iminium activation has been used to great success in Diels-Alder reactions. This example employs an imidazolidinone formed from pehnyalanine and a furanyl aldehyde. It proceeds with the standard exo diastereoselectivity (secondary orbital interactions) and excellent enantioselectivity. The enantioselectivity can be rationalised as shown above. First condensation gives one geometry of iminium cation. The furanyl moiety can accommodate the ethyl group more readily than the benzyl substituent as there are fewer non-bonding interactions (CH2 vs. CH2 bad). The benzyl group can adopt a conformation that allows π-stacking so favours the alkene. 16
  17. 17. This arrangement blocks the top (Re at α- iminium) face. The diene must approach from the bottom (Si) face. The charged iminium species is over the diene (endo) to maximise secondary orbital interactions. Concerted cycloaddition then occurs. There are other forms of organocatalysis that do not involve the formation of a reactive intermediate (enamine or iminium) but involve an adduct/complex. In Nature, hydrogen bonding is important for the formation of secondary structure in proteins but also for molecular recognition and activation ... chemists have mimicked this ... 17
  18. 18. ... to activate aldehydes and ketones in an analogous manner to Lewis acids. Hydrogen bonding results in weaker activation than traditional Lewis acids but has the advantage that the catalysts are more stable and are rarely irreversibly deactivated. Ureas and thioureas are commonly employed in this role. Thioureas are preferred as they do not self-associate as strongly. This is an example of cyanohydrin formation. The thiourea activates the ketone to nucleophilic attack. Trimethylsilyl cyanide is a slightly more user friendly alternative to hydrogen cyanide and protects the cyanohydrin. The story of the discovery of this catalyst is a testament to good science and it is well worth reading the original Jacobsen papers. 18
  19. 19. The next example utilises a thiourea in a related form of catalysis. This is taken from the synthesis of yohimbine, which is used for the treatment of erectile dysfunction. The catalyst controls the enantioselectivity of the wonderfully named ... 19
  20. 20. ... Pictet-Spengler reaction ... ... which is formally a cyclisation reaction (although it actually involves cyclisation to form a 5-ring followed by migration to give the 6-ring). This is an example asymmetric counter- anion catalysis. Effectively an electrostatic attraction between the iminium species and a hydrogen bonded chloride creates a chiral environment of the cyclisation. 20
  21. 21. Question time ... What is the smallest catalyst? It is, of course, a single proton ... or acid catalysis or Brønsted acid catalysis. 21
  22. 22. But how do you make a proton, which in organic terms is an empty 1s orbital, chiral? Its a spherical entity and a sphere cannot be chiral ... Well you attach it to a chiral molecule and rely on the electrostatic attraction between the protonated substrate and the conjugate base to create the necessary chiral environment (or you hope it does not dissociate and that you have a hydrogen bond catalyst). Chiral phosphoric acids and their derivatives have become very useful catalyst in organocatalysis and metal catalysis (where they can be the counter ion). 22
  23. 23. Here is an example of an aza-ene reaction (I guess you can think of this as an enamine version of the Mannich reaction). In this reaction the phosphoric acid acts as a manifold to position and activate the substrates. The acid functionality protonates the imine while the P=O probably hydrogen bonds to the N–H of the enamide. With both the nucleophile and electrophile activated within a chiral pocket good yields and enantioselectivities are observed. Alternatively, in this example the phosphoric acid simply protonates the imine and makes it more electrophilic. The resulting iminium cation is electrostatically attracted to the conjugate base so when the indole attacks in a Friedel-Crafts reaction the bond forming event occurs within a chiral environment. 23
  24. 24. And here is yet another example. This time it is a hetero-Diels-Alder reaction. Once again the imine is protonated to make it more electrophilic and it reacts with the electron rich diene. Not the phenol substituent on the imine. This probably permits to points of interaction between the substrate and catalyst (bifunctional hydrogen bonding). These next two slides reveal how desperately I need to update this section ... when I wrote these slides this was cutting edge with less than a handful of papers ... ... now it is an established area of chemistry that permits some truly remarkable tranformations to be performed (so at least I was right in suggesting this was an area to watch!) 24
  25. 25. Combing organocatalysis with photoredox chemistry permits an exciting method to not only generate radicals under remarkably mild and clean conditions (freeing radical chemistry from the tyranny of organotin compounds) but perform some highly enantioselective reactions. If you like organic chemistry and enantioselective synthesis this is really exciting and I would thoroughly ... ... recommend that you read the work of MacMillan and Corey Stephenson (amongst others). Next lecture ... Synthesis 25