Chapter 2. The Enantioselective Synthesis of α,β-Diamino Acids
2.4 The Johnston Group’s Synthetic Approach Toward α,β-Diamino Acid Derivatives
As discussed in Chapter 1, our group had previous success with BAM•HOTf ligands catalyzing the addition of α-unsubstituted nitroacetates to azomethines (Scheme 37). This success suggested that it may be possible to
59 Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
60 Han, B.; Liu, Q. P.; Li, R.; Tian, X.; Xiong, X. F.; Deng, J. G.; Chen, Y. C. Chemistry 2008, 14, 8094.
61 Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
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63 Rueping, M.; Antonchick, A. P. Org. Lett. 2008, 10, 1731.
Scheme 35. Chen’s Synthesis of α-tetrasubstituted α,β-diamino acids Using a Thiourea Catalyst.
Scheme 36. Shibiskai’s Reaction Utilizing a Dinuclear Ni(II)-Schiff Base Complex.
add α-substituted α-nitroacetates to azomethines, although the use of more sterically hindered nucleophiles would be expected to decrease reactivity. Besides hindering reactivity, the substitution of a hydrogen atom with an alkyl group can be expected to decrease stereoselection (Figure 5) since the distinction in the steric bulk of the groups being differentiated (ester and alkyl) would be diminished (compared to ester and H).
With these concerns in mind, Singh began to investigate this reaction by adding α-methyl tert-butyl nitroacetate to an aldimines using H,Quin-BAM•HOTf (14•HOTf). The reaction led to product formation, albeit with low reactivity and stereoselectivity (Scheme 37).64 The low reactivity and stereoselectivity confirmed the hypothesis about the change in reactivity an α-substituent would bring about.
The general rate enhancement afforded by BAM•HOTf complexes is a combined effect of two orthogonal modes of reactivity. The Brønsted acidic nature of these catalysts serves to activate the electrophilic imine while the Brønsted basic property serves to deprotonate and orient the pronucleophinic nitro-compound prior to the aza- Henry reaction. What this means is that in order to increase the concentration of the active nucleophile in solution, and consequently the reaction rate, either the acidity of the pronucleophile needs to be increased or the basicity of the catalyst needs to be enhanced. From previous studies, it was known that the 4-position of our BAM catalysts has very little effect on stereoselection. So, it was suggested that an electron-donating substituent at the 4-position of the quinoline should increase the electron density of the quinoline ring, and consequently the Brønsted basicity of the catalyst; this seemed like the simplest way to modify the complex to increase the rate of reaction without affecting stereoselectivity in the reaction. Gratifyingly, bis(methoxy) catalyst 18•HOTf provided a considerable increase in conversion and a slight increase in enantioselection, however the reaction still lacked diastereoselection – as such, the results were not optimal (Scheme 38).
64 Singh, A., Vanderbilt University, 2009.
Figure 5 Hypothesis for the Expected Erosion of Diastereoselection when Employing α-Substituted Nitroacetates Compared to their Unsubstituted Analogues
Scheme 37. Singh’s Initial Exploration of α-Substituted Nitroacetate Nucleophiles
In reactions studied using α-unsubstituted α-nitroacetates, unsymmetrical catalysts containing a hindered substrate binding pocket provided higher enantioselection than symmetrical catalysts did. We wondered whether the same increase could be translated to reactions with α-substituted nitroacetate pronucleophiles. Indeed, this was the case that unsymmetrical catalyst 15•HOTf afforded an increase in enantioselection while maintaining an acceptable rate of reaction (vide infra).65 Interestingly, this means that two very different catalysts provided distinct advantages over utilizing H,QuinBAM•HOTf: an increased reaction rate tracked with electron donating quinoline substituents, and increased enantioselectivity was obtained by using an unsymmetrical catalyst.
Essentially, a single new catalyst design was needed that would combine both an increase in reactivity and an increase in enantioselectivity. Figure 6 demonstrates the algorithm Singh took to rationally develop this catalyst.66
65 The unsymmetrical catalyst increased reactivity moderately as well, though to a lesser degree than 18•HOTf. Preliminary, this could be explained from a proximity effect, wherein the bulkier catalyst brings the electrophile and nucleophile closer together, increasing conversion via increasing the concentration of the active catalyst.
66 Figure adapted from ref. 64.
Scheme 38. Increased Quinoline Electron Density Increases Catalyst Activating Ability
Impressively and gratifyingly the rational catalyst design was effective. Unfortunately, diastereoselectivity was still low. It was hypothesized that the steric nature of the ester in combination with the hindered binding pocket may be able to influence diastereoselectivity. Singh investigated esters with varying steric bulk and revealed this hypothesis to be correct (Scheme 39).64 The use of the propofolate 59d afforded high diastereoselection while maintaining reactivity and high enantioselection. This reaction had a wide substrate scope.31
The absolute stereochemistry at the benzylic carbon was the expected outcome based on previous chemistry.
Perhaps most interestingly, X-ray diffraction showed that the syn-diastereomer was synthesized from these
Figure 6. Singh’s Algorithm for the Design of an Optimal Catalyst for the Addition of α-Alkyl Nitroacetates to Imines
Scheme 39. Modulation of Diastereoselection via Ester Size Modification
additions. The production of the syn-diastereomer as the major product was somewhat unexpected since until this point, chiral proton catalyzed additions of nitroalkanes, α-unsubstituted nitroacetates, and nitrophosphonates afforded anti-adducts. While the source of syn-diastereoslectivity at this point is not completely understood, differences in catalyst/nucleophile structure might shed some light on this outcome.
In the case of nitrophosphonates, high anti-diastereoselection was achieved by using bulky nitrophosphonates with either H,Quin-BAM•HOTf or H,4OMeQuin-BAM•HOTf. Figure 7 shows the rationale for the observed anti-selectivity along with an analogous hypothesis for the addition of α-nitro acetates. The important difference in the addition of the nitroacetates is that of the structure of the catalyst and the nature of the ester. It could be hypothesized that the combination of a bulky (anthracene containing) catalyst and the bulky propofol ester help to stabilize the hydrogen bonding of the ester to the catalyst proton (or destabilize a NO2-catalyst hydrogen bonding interaction) thus promoting formation of the observed syn-diastereomer.
To evaluate our model for internal consistency, and also to evaluate the role of the bulky catalyst, it was hypothesized that maintaining a bulky propofolate ester, but using a less bulky catalyst such as 18 would restore the ability of an NO2-catalyst interaction and/or take away any stability afforded by the more sterically demanding catalyst, and in doing so, the anti-diastereomer would be favored. Chapter 4 will be devoted to discussing this hypothesis.
Figure 7. Newman Projection Modeling of Diastereoselection in the aza-Henry Reaction Using Chiral Proton Catalysis.
2.5 The Discovery of a Chiral Proton Catalyzed Diastereodivergent Synthesis of anti α-Substituted α,β-