Download to read offline
PhD Allylation Project
- 1. Enantioselective Synthesis of SubstitutedTetrahydrofurans from Homoallylic Alcohols Ondřej Kysilka
- 2. THFs in NaturalProducts 2
- 3. Allylation with Trichlorosilane ChiralLewis bases: Malkov, A. V.; Kočovský, P. Eur. J. Org. Chem. 2007, 29-36. 3
- 4. Allylation with BifunctionalDisilane Peng, F.; Hall D. G. J. Am. Chem. Soc. 2007, 129, 3070-3071. 4
- 5.
- 6. Allylation with BifunctionalDisilane 6
- 7. Allylation with Disilanes 7 Malkov,A. V.; Kabeshov, M. A.; Barłóg, M.; Kočovský, P. Chem. Eur. J. 2009, 15, 1570-1573.
- 8. Enantioselective Allylation R1 catalyst(loading %) yield (%) ee (%) Ph KENPHOS (10) 37 16 Ph KENAMIDE (10) 23 10 p-F-C6H4 PINDIOX (10) 20 30 p-F-C6H4 PINDY (30) 0 n/a p-F-C6H4 QUINDIOX (5) 4 69 8
- 9. Enantioselective Allylation R1 catalyst(loading %) time yield (%) ee (%) Ph METHOX (20) 7d 52 93 4-FC6H4 METHOX (15) 7d 45 97 4-CF3C6H4 METHOX (15) 7d 55 90 4-NO2C6H4 METHOX (20) 7d 46 94 3-MeOC6H4 METHOX (15) 7d 41 96 4-F-C6H4 QUINOX (20) 9d 45 89 4-CF3-C6H4 QUINOX (20) 9d 50 88 Ph ANET-RR (10) 12h 80 90 3-MeOC6H4 ANET-RR (5) 12h 73 77 4-CF3C6H4 ANET-RR (5) 12h 73 97 C5H11 ANET-RR (5) 12h 80 73 C3H7CH=CH ANET-RR (5) 12h 83 98 Ph ANET-SR (10) 12h 82 96 Ph ANET-SR (1) 24h 70 91 3-MeOC6H4 ANET-SR (5) 12h 71 87 4-CF3C6H4 ANET-SR (5) 12h 79 94 9
- 10.
- 11.
- 12.
- 13. Tetrasubstituted Tetrahydrofurans 13Forman, S.G.;Tooze, R. P. J. Organomet. Chem. 2005, 690, 5863-5866.
- 14.
- 15. Other Disilanes Flamme, E.M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644-13645. 15
- 16. Other Disilanes Trost, B.M.; King S. A. J. Am. Chem. Soc. 1990, 112, 408-422. 16
- 17.
- 18. Acknowledgements Pavel Kočovský Andrei Malkov ColinRobinson Ivana Luštická Jiří Mikušek Joanna Philips Lucie Potucká Maciej Barłóg Michal Májek Mikhail Kabeshov Sigitas Stoncius Thank you, for your attention! 18
- 19.
Editor's Notes
- #3 Substituted tetrahydrofuran moiety is featured in a large number of polyether antibiotics, mycotoxins and other natural products. The framework of these molecules are dominated by the presence of substituted tetrahydrofuran rings ... and... Construction of these compounds is to a large extent, an exercise in the preparation of these rings. A lot of attention has been focussed on the development of efficient and stereocontrolled routes to these fragments. Our group has a long history on the field of organocatalysis and enantioselective allylations. We were wondering if this chemistry could be applied in synthesis of these heterocycles.
- #4 When we treat aldehydes with allyltrichlorosilanes in the presence of lewis base, we get homoallylic alcohols. Recently, we have demonstrated that THESE alcohols, can themselves serve as efficient allylating reagents of aldehydes. In the presence of Lewis acid and another portion of aldehyde they undergo 3.3 SA forming another alcohol, thermodynamically favoured over the first one. The resulting alcohols are popular building blocks in the target-oriented synthesis. In the last few years, a lot of new catalysts have been developed by our and other groups which catalyze this allylation reaction with excellent ees. A further advancement can be achieved by decorating the allylsilane, and thus the resulting homoallylic alcohol, with an additional functionality.
- #5 For example, bifunctional allyldisilane [like this one] would allow stereoselective triple allylation of aldehydes, resulting in a stereocontrolled construction of trisubstituted tetrahydrofurans. The two silicon groups in THIS trichlorosilane have in fact orthogonal reactivities: allytrimethylsilane, as a rule, requires Lewis acid catalysis. On the other hand, allyltrichlorosilyl reagents are activated by a Lewis base. With this disilane, the key stereogenic centers are constructed in the first allylation step. The subsequent, diastereoselective cyclization cascade then requires just a non-chiral Lewis acid. So whats happening here is nucleophilic attack onto the second aldehyde giving this carbocation which undergoes the 3.3 SA. This unmasks the second allylsilane functionality and we close the five-membered ring by the intramolecular allylation
- #6 The first task we had, obviously, was to make this disilane. We started with THP protected propargylic alcohol, deprotonated with butyllithium, and treated with (iodomethyl)trimethylsilane. This alkyne was deprotected and reduced by lithium aluminium hydride giving this allylic alcohol with E configuration on the double bond. We displaced the alcohol with chlorine using N-chloro succinimide or hexachloroacetone with triphenyl phosphine at low temperatures. This chloride was treated with trichlorosilane giving the desired disilane. Alternatively, we used hydrogen and lindlar catalyst for the hydrogenation of the alkyne, which gave us allylic alcohol with Z configuration. And using similar procedure we got chloride and disilane with the Z configuration.
- #7 When we used the trichlorosilane for allylation of various aldehydes, we got the expected homoallylic alcohol. As we said, the key difference between THIS alcohol and the non-functionalized analogues is that we have a hidden allylsilane functionality. When we treate the alcohol with Lewis Acid, this allyl silane is unmasked by the oxonia-Cope rearrangement: here, THIS intermediate contains both the activated carbonyl fragment … and an allylsilane moiety and is set for another intramolecular allylation which gives a mixture of syn and anti tetrahydrofurans. Both of the diastereoisomers have the aryl groups on the same side of the ring with the vinyl group pointing either up or down. When the reaction is run at the room temperature we are getting pretty much equimolar of both diastereoisomers. We briefly screened couple of Lewis acids and solvents and played with the amount of the catalyst and the reaction temperature. Eventually, using the optimized conditions, tin triflate as a lewis acid in THF at -90, we were able to obtain the all syn diastereoisomer almost selectively.
- #8 How does the cyclization work and why can we change the ratio of the syn and anti diastereoisomers simply by controlling the temperature? When we mix THIS homoallylic alcohol with another portion of aldehyde in the presence of lewic acid, we expect them to mirror the analogous crotylation or allylation forming oxycarbenium cation via the six membered transition state. As we already said,the difference here is that now we have another allylsilane functionality.. which is set for another intramolecular allylation which closes the five membered ring. When we look at the kinetic transition state, the positions of all the substituents are already prearranged from the previous 3.3 sigmatropic rearrangement and its 6 membered-chair transition state. We can then assume that at low temperatures, the TMS group stays in the prearranged syn position and as the intramolecular cyclization reaction is probably very fast, we are getting the all syn product. At higher temperatures, this equilibrium becomes important and the TMS group can flip into the more stable, less hindered pseudo axial position. Which eventually gives us the thermodynamic product.
- #9 After we optimized the reaction sequence, it was time to try some of our organocatalysts in the first allylation step to make the homoallylic alcohol enantioselectively. First results were not very promising. We were disappointed by the low ees and also low reactivity of the disilane. The reaction typically took several days to reach the full conversion and thus the yields were low as well, because part of the disilane decomposed during such a long reaction time. The results were however suggesting the N-oxide organo catalysts like QUINDIOX or PINDIOX are probably the way to go.
- #10 We turned to our other N-oxide organocatalysts METHOX and QUINOX. Although the reaction was still slow and again took usually several days, the allylation turned out to be highly enantioselective. QUINOX gave us ees over 80% and METHOX over 90 % for all kinds of different substrates. Still disappointed by the long reaction times we turned to other N-dioxide catalysts. Honestly, much to our surprise not only they gave us very good ees but the reaction was complete overnight. Moreover, these catalysts work even with aliphatic aldehydes and we got reasonable 73% ee for allylation of hexanal and excellent 98 % for allylation of hexenal. We were able to lower the catalyst loading to 5 % without any loss of enantioselectivity and even with 1% loading, ee was still over 90%.
- #11 This is just a small example of tetrahydrofurans we made. The cyclization works with aromatic aldehydes, heteroaromatic and both unsaturated and saturated aldehydes.With certain limitations, we are able to introduce basically any aryl or alkyl moiety on both sides of the ring. As we expected, the chirality is fully transfered during on step cyclization step and the ees of products are either the same of the starting homoallylic alcohols or within the experimental error.
- #12 Our next goal was then prepare tetrasubstituted tetrahydrofurans. In order to do so, we would need this kind of homoallylic alcohols, with the substitution on the other side of the double bond and thus this of trichlorosilane.
- #13 First approach we tried to get this trichlorosilane copied our original reaction sequence with a different starting material. However, the deprotection step gave disappointigly low yields and the trichlorosilylation on the secondary carbon didnt work at all. Using other approach, we started from te propargylic bromide, introduced the TMS moiety and then the alcohol, avoiding the protection and deprotection steps. Next two steps copied the previous sequence, reducti the alkyne displacement of the alcohol with chlorine. Trichlorosilylation, using grignard chemistry this time however failed again.
- #14 We decided then to change our approach and rather thaic n making a new trichlorosilane just modify the homoallylic alcohol we already had. We were not very surprised that coupling with acrylates using Grubbs catalyst 1st generation didn’t work, second generation catalyst gave us yields max around 20-30 % even after tedious optimization. Carbopalladation reaction worked very well however unfortunately giving us this unexpected lactone. Which is a product of double carbonylation of the double bond and cyclization. We are far from giving up however and just recently we got some promising results using old good wittig chemistry.
- #15 Should we succeed, this would open a simple and straightforward way the whole range of natural products like these. Many of really simple substituted tetrahydrofurans have interesting antibacterial, antifungal or antiprotozoal activities. Many of them are cytotoxic against various lines of blood, liver, colon or breast cancer.
- #16 We have also been looking into several other disilanes. Following the reaction sequence we optimized for the first disilane, we made this one which we used for allylation of various aldehydes getting this kind of homoallylic alcohols. Unfortunately, when treated with lewis acid, they didnt give desired dihydrofurans, but just the boring product of Peterson elimination. Getting that far however, we protected the alcohol group, to prevent the elimination. And as we expected, after the allylation step we got these 1,5 diols which also can serve as useful building blocks.
- #17 Another disilane can be made in four simple steps from malonate. This one when used as double allylation, affords this disubstituted tetrahydropyrans. We are currently investigating and optimizing this reaction.
- #18 To conclude, we designed three novel bifunctional disilanes and demonstrated their use in stereoselective allylation of aldehydes to get homoallylic alcohols. These alcohols can be transformed in one step into tetrahydrofurans, tetrahydropyrans and 1,5 diols. These can serve as useful building blocks for synthesis of a whole range of interesting natural products.