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Reports: DNI153428-DNI1: Bronsted Acid-Catalyzed Reactions of Unsaturated Acetals

Pavel Nagorny, Ph.D., University of Michigan

The long-term objective of this study is to develop new organocatalytic transformations of α,β-unsaturated acetals (1, Scheme 1). Brønsted acid-catalyzed reactions of α,β-unsaturated acetals have been extensively used in organic synthesis for a variety of different transformations including [2+4], [3+4] and [5+2] cycloadditions, Nazarov cyclizations and conjugate additions.  The reactivity of α,β-unsaturated acetals (1) often parallels the reactivity of α,β-unsaturated carbonyls as such reactions are often proposed to proceed through unsaturated oxocarbenium ions (2). Such intermediates are isoelectronic to the intermediates 4-6 obtained through the activation of α,β-unsaturated carbonyls via complexation with Lewis or Brønsted acids or the formation of unsaturated iminium ions.  However, unlike the α,β-unsaturated carbonyls, it is significantly more challenging to control the reactivity of α,β-unsaturated acetals using simple organic and inorganic molecules as catalysts.  Our studies are designed to address some of the existing challenges by exploring chiral hydrogen bond donors such as chiral phosphoric acids or thiophosphoramides as the organic catalysts. The results of these studies obtained over the last year are described below:

1) Exploring thiophosphoramide-based Hydrogen Bond Donors (HBD) as the co-catalysts for Brønsted acid-catalyzed [2+4] cycloadditions of  α,β-unsaturated acetals. In these studies our group has developed a new type of organocatalytic ionic [2+4] cycloaddition reaction (Gassman cycloaddition) catalyzed by thiophosphoramides in combination with Brønsted acids. The Grieco group has previously developed a synthetically useful and general protocol for these transformations that relies on the use of a concentrated solution of lithium(I) perchlorate (4.0 M in Et2O) and catalytic amounts of sulfonic acids. Both the presence of lithium(I) perchlorate and catalytic sulfonic acid are essential for the progression of this reaction, and no reaction occurs if one of these components is omitted.  Considering that large quantities of explosive inorganic salts that are required to carry these reactions, protocols avoiding the use of lithium(I) perchlorate are highly desired.  In search of completely organocatalytic transformations, we have discovered that catalytic quantities of organic hydrogen bond donors could serve as an alternative to lithium(I) perchlorate. Thiophosphoramides were identified as the best co-catalysts that could promote the cycloaddition reactions.

The unique catalytic properties of thiophosphoramides were attributed to their ability to form three rather than two hydrogen bonds with the counterion. A variety of cycloadducts were obtained in synthetically useful yields (Scheme 2). In addition, we identified that not only p-TSA, but other Brønsted acids such as HBr and TfOH could be used in combination with thiophosphoramides to execute the reaction. Mechanistic studies were conducted to gain a better understanding of the role that thiophosphoramides play as the co-catalysts of the ionic cycloaddition reactions. Thus, to demonstrate that thiophosphoramides act as HBD-catalysts for the counterion activation, NMR titration studies were conducted (Scheme 3). These studies demonstrated that thiophosphoramides form 1:1 complexes with p-toluenesulfonate anion with an association constant of 73,000 in D-chloroform.  Computational studies indicated that all three NH groups of thiophosphoramide are involved in the formation of a supramolecular complex with the p-toluenesulfonate anion. These promising results prompted us to conduct further evaluation of the potential of thiophosphoramides as the hydrogen bond donors as well as the development of the asymmetric version of these catalysts. Our laboratory is currently pursuing both of these directions.

2) Chiral Brønsted acid-catalyzed enantioselective [2+4] cycloadditions of α,β-unsaturated acetals. Another objective of these studies is to develop asymmetric catalytic transformations proceeding through unsaturated oxocarbenium ions 2 (Scheme 1). The high reactivity of such species coupled with their reduced Lewis basicity renders controlling the enantioselective reactions of 2 by chiral catalysts a great challenge. As a result, only auxiliary-based approaches for the reactions of α,β-unsaturated acetals proceeding through 2 existed prior to our studies.  Our approach relied on the use of chiral Brønsted acids as the catalysts that would promote ionization of α,β-unsaturated acetals and produce a chiral ion pair 2. The chiral anion would then control the selectivity of the unsaturated oxocarbenium ion in cycloadditions or the additions of nucleophiles.  To test this hypothesis, we decided to investigate the possibility of conducting a chiral Brønsted acid-catalyzed [2+4] ionic cycloaddition reaction (Scheme 4). The evaluation of various chiral acids led us to the selection of N-triflyl phosphoramide A. Catalyst A was found not only to promote the cycloaddition reactions (29 – 85% yield), but also provided moderate enantioselectivities (36 – 60% ee). These studies represent the first successful enantioselective catalytic ionic [2+4] cycloadditions of α,β-unsaturated acetals. Our future studies will be focused on expanding the scope of this transformation and understanding the mechanism by which the counterion controls the reactivity of 2. In addition, our group is currently investigating other types of enantioselective reactions involving the intermediacy of 2. Impact: During the first year of ACS-PRF support, the training of one postdoctoral fellow was supported by this grant. This postdoctoral fellow and coworkers have made great progress on the described projects and have generated preliminary results, materials, and spectra, which will serve as a foundation for a variety of other related projects in our group. This will also allow us to pursue new directions in HBD and Brønsted acid catalysis.  Some of the aforementioned results were communicated as articles in Angew. Chem. Int. Ed. and Tetrahedron as well as at the 2014 ACS Meeting at San Francisco.