Chapter 3. A Chiral Proton Catalyzed Biomimetic Hetero-Diels-Alder Reaction
3.3 The Development of a Chiral Proton Catalyzed Hetero-Diels-Alder Reaction
3.3.1 Synthetic Strategy
The proton (H+) is arguably the most common Lewis acid found in nature, and many enzymes use hydrogen bonds (X-H or [X-H]+) to carry out asymmetric transformations with awe-inspiring selectivity. These “natural”
acid catalysts have served over the years as an inspiration to synthetic chemists for the development of both reagent-controlled regioselective and stereoselective biomimetic bond-forming transformations.85
Over the past decade, the Johnston group has been dedicated to investigating what we term “chiral proton catalysis” (vide supra). As mentioned previously, chiral bis(amidine) acid salts have found notable success in
83 For a comprehensive review see: Miller, K. A.; Williams, R. M. Chem. Soc. Rev. 2009, 38, 3160.
84 Sprague, D. J.; Nugent, B. M.; Yoder, R. A.; Vara, B. A.; Johnston, J. N. Org. Lett. 2015, 17, 880.
85 Kirschning, A.; Hahn, F. Angew. Chem., Int. Ed. Engl. 2012, 51, 4012.
Scheme 47. Williams’ Total Synthesis of (-)-Brevianamide B
promoting asymmetric aza-Henry (nitro-Mannich) reactions, nitroalkane alkylations, enantioselective halolactonizations, and most recently asymmetric iodocarbonations via the capture of CO2 by homoallylic alcohols. These successes have established the foundation for chiral proton catalysis in asymmetric reaction development, and have also provided the opportunity to explore mechanistically distinct transformations utilizing the same basic scaffold design (bis(amidines) and their salts), showing that, indeed, chiral proton catalysis can be a general tool for asymmetric catalysis. Based on this, we turned our attention to the application of chiral proton catalysis in natural product synthesis.
Inspired by nature, we were intrigued by the notion that a chiral proton complex might emulate the role of an enzyme in a biomimetic reaction – one in which the small molecule ligand uses the same chemical functionality to achieve activation and stereocontrol much like its larger enzymatic counterpart. The recent success the field has seen suggests that molecules as large as proteins may not be necessary to achieve the high levels of stereoselectivity exhibited in enzyme-mediated reactions.
The Diels-Alder reaction ([4+2] cycloaddition) is one of the most powerful transformations in synthetic organic chemistry, allowing for the rapid generation of complex six-membered rings with multiple stereocenters in a single step. The growing number of naturally occurring compounds with structures resembling Diels-Alder adducts have stimulated numerous biosynthetic proposals involving enzyme-mediated [4+2] cycloadditions.86 At least two potential Diels-Alderases have been characterized,87,88 a definite enzyme mediated [4+2] cycloaddition has just been discovered,89 and the mechanistic details of another standalone natural Diels-Alderase has very recently been reported.90,91
As described earlier, a biological Diels-Alder reaction was proposed by both Sammes and Williams to be responsible for the formation of the brevianamide diazabicyclo[2.2.2]octane core. That this hypothesis is plausible was further supported by both synthetic and biological studies. Furthermore, the intervention of a Diels-Alderase has been suggested to account for the selective formation of the major metabolite, brevianamide A, as well as the exclusive anti diastereoselectivity seen in these natural products (vide supra). Although brevianamide B has been previously synthesized in enantioenriched form, to the best of our knowledge there has been no attempt to carry out the proposed biosynthetic Diels-Alder reaction enantioselectively. Therefore, this hypothetical cycloaddition seemed like a good inspiration from which to develop a synthetic “Diels-Alderase”.
86 For a recent, very insightful review on the field: Klas, K.; Tsukamoto, S.; Sherman, D. H.; Williams, R. M. J. Org. Chem. 2015, 80, 11672.
87 Auclair, K.; Sutherland, A.; Kennedy, J.; Witter, D. J.; Van den Heever, J. P.; Hutchinson, C. R.; Vederas, J. C. J. Am. Chem. Soc.
2000, 122, 11519.
88 Watanabe, K.; Mie, T.; Ichihara, A.; Oikawa, H.; Honma, M. J. Biol. Chem. 2000, 275, 38393.
89 Zheng, Q.; Guo, Y.; Yang, L.; Zhao, Z.; Wu, Z.; Zhang, H.; Liu, J.; Cheng, X.; Wu, J.; Yang, H.; Jiang, H.; Pan, L.; Liu, W. Cell Chem Biol 2016, 23, 352.
90 Byrne, M. J.; Lees, N. R.; Han, L. C.; van der Kamp, M. W.; Mulholland, A. J.; Stach, J. E.; Willis, C. L.; Race, P. R. J. Am. Chem.
Soc. 2016, 138, 6095.
91 Minami, A.; Oikawa, H. The Journal of antibiotics 2016. doi: 10.1038/ja.2016.67.
Based on the knowledge gained throughout the lab from our continuous studies on the aza-Henry reaction, the putative brevianamide Diels-Alder intermediate (in Figure 17) was thought to be a feasible candidate for catalysis with BAM ligand-protic acid complexes. Therefore, we had hoped to investigate a [4+2] cycloaddition in the context of a very specific system – that which would lead to the diazabicyclic core. The relative planarity of the 2-hydroxypyrazinone moiety, analogous to the N-Boc imines, was envisioned to permit access to the sterically congested BAM chiral pocket (Figure 18). This intermediate also offers multiple Lewis basic sites for proton binding, a prerequisite for high enantioselectivity in the catalyzed aza-Henry reaction. With these characteristics
in mind, the synthesis of the enantioenriched core of the brevianamides seemed to be a real possibility.
In order to efficiently synthesize the bicyclooctane core, the chiral proton catalyst must be able to direct both enantio- and diastereocontrol of the hetero-Diels-Alder reaction. Chelation of the pyrazinone amidate to the BAM-acid complex is envisioned to occur in a bidentate manner, analogous to the stereochemical model developed for N-Boc imines that was adopted for the aza-Henry reaction. The BAM ligand must then effectively destabilize the transition state formed by approach of the tethered dienophile from one face of the planar pyrazinone relative to the opposite face in order to give enantioselection (Figure 19). If facial discrimination is accomplished, then the use of the opposite enantiomer of the BAM catalyst would also furnish the opposite enantiomer of the Diels-Alder adduct, providing access to the cores of both brevianamide A and B.
Figure 18. Lateral Application of Bis(Amidine) Catalyst Design Features to the Hetero-Diels-Alder Reaction
The diastereoselectivity of the reaction also must be considered, and is determined by the preference for the endo or exo orientation of the prenyl olefin in the transition state of the reaction (Figure 20). The endo transition state is favored in the thermal variant of this reaction (vide supra), which produces the syn configuration at C19 (see Figure 16 for nomenclature). Therefore, the catalyst will be called upon not to enhance, but rather completely reverse the endo:exo relationship from the thermal reaction. To allow access to the brevianamide core, this is critical. However, in the presence of high enantioselection for the core, and high syn selectivity, this would prove useful to synthesizing other related alkaloids which are postulated to be synthesized biologically in the same way.
Utilization of a chiral proton complex to catalyze this Diels-Alder reaction would not only provide the first enantioselective biomimetic synthesis of this class of natural products, but would also support the chemical feasibility of this relatively unknown biological [4+2] reaction. It should be noted that we are not suggesting that the demonstration of a chiral proton catalyzed [4+2] cycloaddition to form the core unequivocally proves the existence of a Diels-Alderase in nature, but rather would shed additional light onto the biosynthesis of this inspiring, and structurally intriguing family of alkaloids. Furthermore, it would provide a compelling basis to further explore the biosynthesis of these natural products. In addition to the intriguing biosynthetic possibilities that would result from these studies, the work has intrinsic synthetic value too. That is, if successful, this would be a rare example of an enantioselective hydrogen bond-mediated inverse electron demand aza-Diels-Alder reaction.
Figure 19. BAM•HX:Azadiene Complex – Diene Facial Discrimination Leads to Opposite Enantiomers of the Core.
Figure 20. Model for endo vs. exo Selectivity