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New Developments in Enantioselective Brønsted Acid Catalysis with Strong Hydrogen Bond Donors

Caroline Dorsch and Christoph Schneider

Department of Chemistry, University of Leipzig, Leipzig, Germany

1.1 Introduction

Brønsted acid catalysis, the acceleration of organic reactions with hydrogen bond donors, is a fundamental principle in organic chemistry. It is based upon the protonation to a Brønsted basic substrate upon which its lowest unoccupied molecular orbital (LUMO) orbital is lowered and thus activated toward nucleophilic attack. Early on, it was shown that carbon-carbon bond-forming processes can as well be accelerated by Brønsted acid catalysis like in aldol and Diels-Alder reactions. Quite surprisingly, however, the development of enantioselective Brønsted acid catalysis with chiral hydrogen bond donors is a relatively new field of little more than the last two decades. In 1998, Jacobsen reported the Strecker reaction of aldimines and hydrogen cyanide catalyzed by a bifunctional, chiral thiourea catalyst [1]. This seminal report laid the foundation for the development of a broad range of enantioselective, thiourea-catalyzed carbon-carbon bond-forming reactions [2]. In 2003, Rawal established the capacity of chiral diols to act as hydrogen bond donors for enantioselective hetero Diels-Alder (HDA) and Mukaiyama aldol reactions [3]. Subsequently, chiral, bifunctional squaramides were introduced as hydrogen bond donors with a defined distance of the two hydrogen bonds relative to each other in close analogy to the thioureas [4].

The earlier mentioned chiral catalysts display rather weak Brønsted acidity with pKa values (in dimethyl sulfoxide [DMSO]) ranging between 12 (squaramides) and 18 (diols) and are proposed to catalyze the respective reactions via hydrogen bonding. On the other hand, much stronger and hence more active chiral Brønsted acids have been developed recently that activate the substrates through protonation and formation of mostly hydrogen-bonded ion pairs. In groundbreaking work published independently by Akiyama [5] and Terada [6] in 2004, the preparation and the first use of 1,1´-bi-2-naphthol (BINOL)-derived, chiral phosphoric acids (CPA) in Mannich reactions have been documented (Scheme 1.1). Their higher Brønsted acidity (pKa = 3.4 (DMSO), 13.3 (MeCN)) and the rigid chiral BINOL backbone make them powerful chiral catalysts, in particular, for imine addition reactions. In addition to the acidic OH moiety, the Brønsted basic phosphoryl oxygen atom provides the opportunity for bifunctional activation due to additional hydrogen bonding of the nucleophile resulting in a highly ordered transition state assembly of nucleophile and electrophile. These seminal reports have provided the basis for a wealth of subsequent applications of these catalysts [7].

Scheme 1.1 BINOL-based phosphoric acid-catalyzed Mannich reaction [6].

It is important to emphasize here the role of the bulky 3,3´-aryl groups within the backbone of the catalyst, which extends the C2-symmetry of the BINOL architecture into space and thereby creates an enlarged chiral pocket in which the reaction takes place with high enantiofacial control. Due to their basicity, imines are ideal substrates in that respect, which are readily protonated and form closely associated ion pairs composed of iminium cations hydrogen bonded to chiral phosphate anions.

In order to also activate less basic substrates such as carbonyl compounds, the phosphoric acid catalysts have been modified into more acidic N-triflyl phosphoramides (NPA) (pKa = -3.4 (DMSO), 6.4 (MeCN)). With NPAs in hand, Yamamoto was able to catalyze the Diels-Alder reaction of silyloxy dienes and a,ß-unsaturated ketones with excellent enantioselectivity, low catalyst loading, and at a low temperature (Scheme 1.2) [8].

Scheme 1.2 N-triflyl phosphoramide-catalyzed Diels-Alder reaction [8].

This class of strongly acidic Brønsted acids has later been routinely employed as an alternative to the classical phosphoric acids whenever higher Brønsted acidity was required [9]. Further modification of the phosphoryl oxygen moiety into the corresponding thiophosphoryl and selenophosphoryl groups is easily possible and results in yet enhanced Brønsted acidity of the N-triflyl phosphorthioamides and N-triflyl phosphorselenoamides, respectively, e.g. for protonation and Mukaiyama aldol reactions [10].

In this chapter, we will focus on select newer applications of these catalysts in recent years as well as further developments toward yet stronger and more refined chiral Brønsted acids. For ease of understanding, we will use the abbreviation CPA for chiral phosphoric acids and NPA for N-triflyl phosphoramides and specify only the different 3,3´-aryl groups (Ar) employed in the individual reactions. Due to limited space, this chapter cannot possibly be comprehensive and therefore reflects more a personal selection of the authors. For more detailed information on the characteristics and applications of BINOL-phosphoric acids and amides as Brønsted acid catalysts and further developments in the field, the reader is referred to excellent review articles that have appeared recently [7, 9].

1.2 Chiral BINOL-Phosphoric Acids in Dehydration Reactions

The early focus of CPA catalysis was the activation of imines, aldehydes, and ketones. In recent years, other substrates have been studied as well that are prone to Brønsted acid activation. For example, benzyl alcohols are easily dehydrated into benzyl cations under Brønsted acid catalysis and may subsequently be reacted with a broad range of nucleophiles. The principal difference in comparison to the earlier mentioned substrates concerns the nature of the ion pair. Whereas iminium and oxonium phosphate ion pairs are closely connected through a strong hydrogen bond, the benzyl phosphate ion pair is only loosely held together by purely electrostatic interactions lacking any directional interaction through a hydrogen bond. Thus, it is anything but easy for the chiral anion to provide an effective chiral environment that results in high enantioselectivity of the ensuing reaction.

To overcome this problem, an ortho-phenol moiety has been introduced into the benzyl alcohol and substrates such as 1 have been investigated. Upon Brønsted acid-catalyzed dehydration, the resulting cation may be hydrogen bonded to the chiral phosphate anion X* through the adjacent phenol moiety (Figure 1.1). The prevailing resonance structure of this cation is the corresponding ortho-quinone methide 2 connected to the chiral phosphate anion X* via a hydrogen bond [11].

Figure 1.1 Dehydration of ortho-hydroxy benzyl alcohols 3 to ortho-quinone methides 2.

In the last years, the Schneider group investigated this concept in detail and developed a broad range of cycloaddition reactions using hydrogen-bonded ortho-quinone methides as transient intermediates [12]. Thus, a broad variety of benzannulated oxygen heterocycles 4-9 have been prepared in a highly straightforward fashion with excellent enantioselectivity starting from ortho-hydroxy benzyl alcohols 1 and enol-rich ß-diketones 3, aldehydes as well as enamides and a-diazo ketones (Scheme 1.3). The dihydrocoumarins 7 and dihydrofurans 8 were obtained with good cis-diastereoselectivity as well, whereas the acetamidotetrahydroxanthenes 9 were isolated even as single diastereomers.

Scheme 1.3 Phosphoric acid-catalyzed cycloadditions of ortho-quinone methides [12].

The earlier depicted reaction with 1,3-cyclohexane dione 3 (Scheme 1.4) has been investigated in detail by thorough kinetic, spectroscopic, and theoretical studies providing a detailed mechanistic picture. After a rate-determining dehydration event to furnish the hydrogen-bonded ortho-quinone methide 2, the cycloaddition took place in a concerted, yet highly asynchronous manner with the C-C-bond formation preceding the C-O-bond formation. It proved to be mandatory for reactivity as well as enantioselectivity that the dienophile carried an acidic proton capable of hydrogen bonding to the phosphoric acid catalyst in accord with the assumption of a bifunctional activation of both reaction partners in a highly ordered transition state.

Scheme 1.4 Cooperative Rh-/phosphoric acid-catalyzed cycloaddition with diazo esters [13].

This concept was subsequently merged with transition metal catalysis. Thus, it was shown that a cooperative Rh-/phosphoric acid-catalyzed reaction of ortho-quinone methides with diazo esters 10 delivered densely substituted and highly functionalized chromanes and oxa-bridged dibenzooxacines 11 with good yields, excellent...