Keck asymmetric allylation is an organic reaction in which an aldehyde can be converted to a homoallylic alcohol with high enantioselectivity. It is named after the University of Utah chemist Dr. Gary E. Keck. This reaction is also known as catalytic asymmetric allylation (CAA). The catalyst used in this reaction is a complex of (R) or (S)-BINOL (1,1'-Bi-2-naphthol) and Ti(OiPr)4. The catalyst has been given an acronym "BITIP" derived from the words BINOL and Titanium isopropoxide. There are 4 methods of preparation of the catalyst. They vary in the proportions of BINOL and Ti(OiPr)4 as well as catalytic amounts of CF3COOH (TFA).
BINOL and Ti(OiPr)4 (1:1), 4 Å MS (400 mg/mmol of aldehyde)
BINOL and Ti(OiPr)4 (2:1), 4 Å MS (400 mg/mmol of aldehyde), TFA (0.003 equivalent with respect to the aldehyde)
BINOL and Ti(OiPr)4 (2:1), 4 Å MS (400 mg/mmol of aldehyde)
BINOL and Ti(OiPr)4 (2:1)
E. J. Corey proposed a transition state structure of the catalyst (figure at the right) bound to the aldehyde where he invoked the idea of formyl C-H---O hydrogen bonding to
As there are not enough direct proofs of this formyl hydrogen bonding apart from the crystal structures, this stereochemical model is still not widely accepted to explain the absolute stereochemistry.
Interestingly, molecular sieves used in this reaction is probably serving the purpose of providing some water molecules in the reaction mixture (except method D). Mikami and co-workers proposed that the active catalyst can only be formed due the presence of water molecules in the molecular sieves. This indicates the water molecules are probably acting as acid/base catalyst. Without the molecular sieves, lower yield of the reaction was observed. From the studies done by Keck and co-workers, the role of the molecular sieves seems to be more complex than just providing water molecules or sequestering MeOH (when B(OMe)3 is added as an additive). Molecular sieves are also necessary for higher enantioselectivity.
Catalytic amount of trifluoroacetic acid or even triflic acid is used in this reaction (only in method B). Proton sources play an important role in the formation of the active catalyst by protonating the isopropoxide groups bound to titanium and thereby making the Ti-O bond more labile.
Sometimes it is preferable to use some additives such as iPrsBEt2 or B(OMe)3 to increase the rate of the reaction as this reaction ideally takes about 3-7 days to go to completion. The role of B(OMe)3 was studied by Keck and co-workers. B(OMe)3 probably binds with free isopropanol molecules in the reaction mixture and the liberated MeOH from the borate esters is sequestered by the molecular sieves, thereby facilitating the activity of the catalyst which in turn increases the rate and yield of the reaction.
1. Keck and co-workers used this reaction in their elegant synthesis of the antitumor natural product epothilone B. The C15 stereocenter was set up using the CAA reaction.
2. The example reaction is taken from the synthesis of bryostatin 1 by Keck and co-workers. The C5 stereocenter was established with CAA. Later on, this stereocenter was used for the stereochemical induction on C3 and C7 carbons. The structure of bryostatin 1 is given below:
For the seminal publications on CAA, see:
1. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468.
2. Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 49, 7827-7828.
3. Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543-6544. (discussion on non-linear effect)
4. Keck, G. E.; Krishnamurthy, D.; Roush, W. R.; Reilly, M. L. Org. Synth. 1998, 75, 12.
For the transition state model by Corey, see:
4. Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321-1329.
For the role of molecular sieves and additives, see:
5. Mikami, K. Pure & Appl. Chem. 1996, 3, 639-644.
6. Kurosu, M.; Lorca, M. Synlett 2005, 7, 1109-1112.
7. Heumann, L. V.; Keck, G. E. Org. Lett. 2007, 21, 4275-4278.
For related applications of the catalyst, see:
8. Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638-7639.
9. Professor Douglass Taber's article in Organic chemistry portal: http://www.organic-chemistry.org/Highlights/2009/06July.shtm (synthesis of epothilone B)
10. Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org. Chem. 2008, 24, 9675-9691. (synthesis of epothilone B)
11. Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.; Covel, J. A. J. Am. Chem. Soc. 2011, 4, 744-747. (synthesis of bryostatin 1)