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123713AB lecture04


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Use of stoichiometric amounts of a chiral source. The usual suspects will be discussed, including borane reagents (mostly pinene derivatives) and the Brown allylation.

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123713AB lecture04

  1. 1. With both substrate control and the use of chiral auxiliaries the stereo-control element has been part of the substrate.This has obvious limitations; the must be an existing stereogenic element or a point of attachment for the auxiliary. What happens if we have no stereochemistry in our molecule? Or we don’t want to add two steps to our synthesis (attachment/removal of auxiliary)? We could add the stereocontrol element to the reagent ... The molecule above is the primary odour molecule responsible for the smell of musk and has been used in perfumes for thousands of years. Synthetic muscone saves the poor musk deer from being slaughtered. 1
  2. 2. ... or in cartoon form ... The reagent contains the stereochemical information and its interaction with the substrate creates diastereomeric transition states; one will be lower in energy and will lead to the preferred product. The advantage of this form of control is that we no longer require any stereochemical information in the substrate ... One asymmetric synthesis of muscone involves the conjugate addition (1,4- addition) of a cuprate to an enone. This can be achieved in high enantioselectivity by adding a chiral amino alcohol. Now, instead of the substrate controlling which face of a molecule the reagent can approach, the reagent controls which face the molecule can approach ... 2
  3. 3. ... the disadvantage is that it can be quite wasteful; we need a stoichiometric quantity of the chiral reagent and unless we can recycle/recover the reagent we are throwing a lot of chirality away. Chiral organoboranes have long held a powerful position in the pantheon of chiral reagents. The reason for this is the easy access to chiral derivatives from natural ‘chiral pool’ materials by simple hydroboration coupled to the utility of these reagents in a number of reactions. The reagent above is called alpine borane and is formed from pinene. It is a chiral reductant. 3
  4. 4. This reagent reduces ketones with good enantioselectivity. Boron is group 13 so only has 6 valence electrons in neutral compounds. It is a Lewis acid. It will coordinate with a lone pair of electrons on the ketone. The coordination activates both the ketone, making the carbonyl more electron deficient, and activates the reductant. Rehydridisation of the boron from sp2 to sp3 lengthens the C–B bond making the reagent more nucleophilic. Coordination links substrate and reagent together. The reaction then proceeds through a boat-like transition state. The enantioselectivity (or facial selectivity) is governed by the minimisation of 1,3-diaxial interactions across the ring. So the ketone approaches the borane so that the small group is parallel to the methyl of the reagent as shown above. 4
  5. 5. An example of an analogous reagent being used in the synthesis of a pharmaceutical is taken from this synthesis of fluoxetine (or Prozac). This example replaces alpine borane with (ipc)2BCl (ipc = isopinocampheyl). This reagent is more sterically demanding (resulting in higher enantioselectivity) and more Lewis acidic (higher reactivity) thanks to the electron-withdrawing chlorine. The transition state is thought to be the same as alpine borane. Coordination of the ketone sets up a boat-like transition state with the smallest ketone substituent adopting the pseudo-axial position to minimise the 1,3-diaxial interactions across the ring. As you can see the reaction is very effective. 5
  6. 6. Pinene makes an excellent molecule for the synthesis of these chiral reagents. It is a cheap and abundant source of chirality (European pine trees produce a more enantiomerically enriched sample than North American pines). Hydroboration occurs on the least sterically hindered face of the alkene (anti the bulky dimethyl bridge). The boron adds to the least substituted, more nucleophilic, carbon. The bulk of pinene means hydroboration only occurs twice to give (ipc)2BH. This reagent undergoes disproportionation on treatment with TMEDA (N,N,N’,N’- tetramethylethylenediamine) to give ipcBH2. Note how the sign of the optical rotation changes between the two molecules even though each contains the same stereogenic centres ... 6
  7. 7. Organoboranes be employed in enantioselective oxidations as well as reductions. Good results can be obtained with cis-alkenes and (ipc)2BH as shown above. While I will not go through the origin of the stereoselectivity here you should be able to start to rationalise it for yourself. First you need to deduce the favoured conformation of the two ipc units. Then how they approach the alkene. (ipc)2BH only gives good results with cis- alkenes; non-bonding interactions prevent it approaching trans-alkenes. IpcBH2 gives its best results with trans- alkenes and trisubstituted alkenes. It is less sterically demanding, which aids reactivity, but at a slight cost to enantioselectivity. 7
  8. 8. For those of you who are interested this is the start of understanding the enantioselectivity in the the hydroboration reaction ... There is much ‘harder’ or should that be ‘in depth’ version of this course on the horizon (it just takes an awfully long time to prepare all the diagrams) Probably the most important use of boron reagents in asymmetric synthesis is in the aldol reaction. Here they permit the formation of a C–C bond and up to two new stereocentres with remarkably high yields, diastereo- and enantioselectivity. (ipc)2BOTf (Tf = triflate = SO2CF3) is readily prepared from the organoborane. 8
  9. 9. It is occasionally argued that this an example of chiral auxiliary control. As we shall see a chiral enolate is formed by combining the ketone and reagent. This is then reacted with the achiral aldehyde. Personally, as we never isolate the chiral enolate and the ipc subunit is lost from the product during work-up I think this is more a case of chiral reagent ... but it doesn’t really matter. So what is going on? Why is the reaction so effective? 9
  10. 10. The first step is the formation of the boron enolate. The geometry of the enolate is of great importance. Under normal conditions the Z(O)-enolate (shown above) is favoured. The mechanism for enolate formation involves activation of the carbonyl group by coordination to the boron followed by deprotonation. The aldol reaction then proceeds through the classic Zimmerman-Traxler chair-like transition state. Coordination of the boron enolate with the the aldehyde activates both the electrophile (Lewis acid activation) and the nucleophile (rehybridisation of boron from sp2 to sp3 lengthens the B–O bond feeding electrons towards the oxygen). 10
  11. 11. O B O H H H H H H R2 R H O B O H H H H H R2 R ≡ ≡ OaldehydeenolateO OaldehydeenolateO L H S L H S L H S SL H 'eclipsed' +2.3 kcal mol–1 'staggered' 11
  12. 12. O B O H H H H H H R2 R O B O H H H H R2 H R H disfavoured interaction +1.4 kcal mol–1 vs favoured good separation 12
  13. 13. The geometry of the enolate fixes the position of the enolate substituents and the methyl group must be pseudo-axial. The orientation of the aldehyde can change but, as you should be aware, its substituent will adopt the pseudo-equatorial position to minimise 1,3-diaxial interactions. The only choice is which face of the aldehyde is attacked (re or si) ... ... this is controlled by the pinene units. The favoured conformation of two pinenes is that shown above. In many respects the most important pinene is the pseudo axial pinene. The equatorial pinene is only playing a support role. The axial pinene wants to minimise 1,3-diaxial interactions so the hydrogen atom is directed towards the ring ... 13
  14. 14. This slide tries to demonstrate the various conformations of the reagent based on minimising 1,3-diaxial interactions (and thus fixing the conformation of the axial pinene). Once the conformation of the boron reagent has been sorted we then have to look at the constituents of the chair-like transition state. The enolate has an axial substituent. To minimise non-bonding interactions this will be orientated away from the methyl of the pinene. So the aldehyde must approach from the same face as this methyl group. Thus the enolate attacks the si face of the aldehdye. 14
  15. 15. If you want to find an example of this sort of chemistry in action look for the work of Paterson, he has undertaken some remarkable total syntheses that are often built on the power of the aldol reaction ... This example is from the synthesis of laulimalide, a marine natural product. This example is of the challenging acetate aldol (a methyl ketone so there is no substituent on the enolate). Such examples frequently have lower stereoselectivities than the normal propionate examples ... the influence of the methyl substituent on the transition state is surprisingly important. Anyways, this example shows how the reagent can control diastereoselectivity in a complex substrate. 15
  16. 16. Boron reagents have found considerable use in enantioselective allylation and crotylations, a powerful route to functionalised alcohols. Hopefully you can already see the similarity between these reagents and the aldol reaction ... conceptually, a methylene group has replaced the oxygen of the enolate otherwise everything is the same ... Coordination of substrate and reagent activates both the electrophile and the nucleophile. A six-membered Zimmerman-Traxler chair- like transition state is formed. The ligands on the boron will control the enantioselectivity while the geometry of the crotyl alkene will control the diastereoselectivity. 16
  17. 17. As with the aldol reaction. The position of the alkene substituents is fixed (like the enolate substituents). The only option we have is the aldehyde substituent. It will adopt the pseudo-equatorial position in preference to the pseudo-axial conformation in order ... ... to minimise unfavaourable 1,3-diaxial interactions. The geometry of the alkene will control the diastereoselectivity of the reaction. Hopefully you can see that the E-alkene results in formation of ... 17
  18. 18. ... the anti product (RE is on the opposite face of the product to the hydroxyl group) while the Z-alkene results in the formation of the syn product. This stereospecificity is key Type 1 crotylations and boron-mediated aldol reactions. If you do not understand it see me. Now we need to look at controlling the enantioselectivity. Once again this can be achieved with the use of pinene derivatives. These are readily formed by hydroboration followed by addition of the appropriate crotylmetal reagent. 18
  19. 19. As expected (see aldol reaction) the Z- crotyl reagent results in the formation of the syn product. Remember: geometry of the alkene controls the relative stereocehmistry or diastereoselectivity. The pinene subunit controls the absolute stereochemistry or enantioselectivity. The reaction proceeds through the Zimmerman-Traxler chair-like transition state. The aldehyde will be orientated so that its substituent is equatorial. The crotyl reagent is bulkier than the aldehyde (CH2 vs. O) so the favoured conformation has it away from the methyl groups of the pinene (or the aldehyde approaches from the same face as the methyl groups). 19
  20. 20. The use of allyl/crotyl pinene-derived boranes is known as the Brown allylation or crotylation. Changing the geometry of the alkene will result in the formation of the anti diastereomer. The absolute stereochemistry (the hydroxyl stereocentre) will remain the same. These reagents give good enantio- and diastereoselectivities but are moisture sensitive so require careful handling (prepare on day of use). Tartaric acid derivatives are known as the Roush reagents. These give slightly reduced stereoselectivities compared to the Brown reagents but are easier to use. As we can see, they follow the same principles with the reaction proceeding through a closed chair-like transition state so the geometry of the alkene controls diastereoselectivity and the tartrate controls absolute stereoselectivity ... 20
  21. 21. ... the control of the absolute stereochemistry is thought to be control by an electronic effect rather than simple steric hindrance. The aldehyde approaches anti to the lower ester in order to minimise the interactions of the oxygen lone pair of electrons. There are many asymmetric allylation/ crotylation reagents available. Amongst the most successful of the new generation are the silicon based reagents of Leighton. An example of the use of these is found in the synthesis of this potential drug candidate ... 21
  22. 22. ... these reagents operate in the same manner as the boranes we have just covered. The reactions proceed through a closed chair-like transition state. The geometry of the alkene controls the relative stereochemistry (syn or anti) while the diamine (a common, easily accessible, ‘chiral pool’ material) controls the absolute stereochemistry. These reagents are air-stable solids and are commercially available. More information can be found in: J. Am. Chem. Soc. 2011, 133, 6517 22