Jacobsen reports another interesting example of organocatalysis, here using a chiral guanadinium salt to catalyze the enantioselective Claisen rearrangement.¹ As an example, Reaction 1 proceeds in 6 days at 30 °C to give 81% yield with an ee of 84%. The system is also diastereoselective, so that Reaction 2, run for 6 days at 40 °C, gives an 82% yield with a diastereomeric ratio of 16:1 and an ee of 81%.

B3LYP/6-31G(d,p) computations provide some insight. The uncatalyzed reaction of 1 to give 2 is predicted to be exothermic by 16.1 kcal mol^-1, with an activation energy of 25.9 kcal mol^-1. Using N,N’-dimethylguanidnium as a model for the catalyst (and with no counter anion and no treatment of solvent – hexanes in this case), they find a complexation energy of almost 27 kcal mol^-1 for forming 3. 3 exhibits (See Figure 1) three hydrogen bond-like interactions – one N-H bifurcates to interact with the carbonyl oxygen and (a very long interaction) to the other oxygen. The product complex 4 also shows three hydrogen bond-like interactions, with an overall exothermicity of -14.7 kcal mol^-1. The complexed transition state 5 has two normal length hydrogen bonds, with an activation energy above 3 of 20.6 kcal mol^-1. Thus the complex lowers the barrier by about 5 kcal mol^-1, indicating the catalytic effect. They have not however addressed the enantioselectivity.

3	5
4

Figure 1. B3LYP/6-31G(d,p) optimized geometries of 3-5.

References

(1) Uyeda, C.; Rötheli, A. R.; Jacobsen, E. N., "Catalytic Enantioselective Claisen Rearrangements of O-Allyl β-Ketoesters," Angew. Chem. Int. Ed., 2010, 49, 9753–9756, DOI: 10.1002/anie.201005183

InChIs

1: InChI=1/C10H14O3/c1-3-7-13-9-6-4-5-8(9)10(11)12-2/h3H,1,4-7H2,2H3
InChIKey=NASFSRKGDOBHIX-UHFFFAOYAC

2: InChI=1/C10H14O3/c1-3-6-10(9(12)13-2)7-4-5-8(10)11/h3H,1,4-7H2,2H3/t10-/m0/s1
InChIKey=QXKXLNGEBVMWLH-JTQLQIEIBT

There remains still new territory to explore even with such well-known reactions as the Claisen rearrangement. Jacobsen reports a catalyzed Claisen rearrangement where the catalyst is urea-based.¹ Catalyst 1 produces modest to very reasonable % conversion in a series of simple Claisen rearrangements, as shown in Table 1.

Table 1. Claisen Rearrangements

With the chiral catalyst 2, the Claisen rearrangement is both catalyzed and proceeds with large enantiomeric excess, as shown in the representative example Reaction 1.

Jacobsen and Uyeda also reported the transition state for a model Claisen rearrangement catalyzed by a model guanidinium ion (Reaction 2) computed at B3LYP/6-31G(d). I have reproduced this calculation and the calculations for the both the catalyzed and uncatalyzed rearrangements, shown in Figure 1. In email communication with Dr. Jacobsen, I was able to confirm these energies against their own unpublished results.

Uncatalyzed Reaction 2
Reactant: 0.0	TS: 25.73
Product 1: -11.04	Product 2: -13.69
Catalyzed Reaction 2
Reactant: 0.0	TS: 21.09
Product 1: -12.36	Product 2: -12.80

Figure 1. B3LYP/6-31G(d) optimized structures of the critical points of uncatalyzed and catalyzed Reaction 2. Relative energies in kcal mol^-1.

The structures show the beneficial hydrogen bonds between the guanidinium anion and the carbonyl oxygens (or the ether oxygen of the reactant). In progressing from the transition state, both reactions first gives Product 1. This product conformer can than rotate to give the lower energy conformer Product 2. The activation energy of the catalyzed reaction is 4.64 kcal mol^-1 lower than for the uncatalyzed reaction, demonstrating the benefit of the complexation in the transition state.

I want to thank Dr. Jacobsen and his graduate student Chris Uyeda for sharing their computational results with me for the preparation of this blog post.

References

(1) Uyeda, C.; Jacobsen, E. N., "Enantioselective Claisen Rearrangements with a Hydrogen-Bond Donor Catalyst," J. Am. Chem. Soc., 2008, 130, 9228-9229, DOI: 10.1021/ja803370x.