Jon C. Antilla

Chiral Brønsted Acid-Catalyzed Allylboration of Aldehydes

The catalytic enantioselective allylation of aldehydes is a long-standing problem of considerable interest to the chemical community. We disclose a new high-yielding and highly enantioselective chiral Brønsted acid-catalyzed allylboration of aldehydes. The reaction is shown to be highly general, with a broad substrate scope that covers aryl, heteroaryl, alpha,beta-unsaturated, and aliphatic aldehydes. The reaction conditions are also shown to be effective for the catalytic enantioselective crotylation of aldehydes. We believe that the high reactivity of the allylboronate is due to protonation of the boronate oxygen by the chiral phosphoric acid catalyst.

Chiral calcium VAPOL phosphate mediated asymmetric chlorination and Michael reactions of 3-substituted oxindoles.

We disclose a novel high yielding and highly enantioselective chiral calcium VAPOL phosphate-catalyzed chlorination of 3-substituted oxindoles with N-chlorosuccinimide (NCS). The reaction conditions are also shown to be effective for the catalytic enantioselective Michael addition of 3-aryloxindoles to methyl vinyl ketone.

Highly enantioselective catalytic benzoyloxylation of 3-aryloxindoles using chiral VAPOL calcium phosphate.

3-Hydroxy-2-oxindoles are structural motifs present in a number of natural products and biologically active compounds.[1, 2] Among these molecules, 3-aryl-3-hydroxyoxindoles represent an important class of molecules that have found broad applications in medicinal chemistry. One such example is SM-130686 (Scheme 1), a compound exhibiting potent activity with respect to growth hormone release.[2a] The absolute configuration of the hydroxy group at the C3 position was shown to further modulate the biological activity.[2c] It is therefore of high importance to introduce asymmetry at the C3 position with high enantiocontrol. To date, only a limited number of approaches have been reported, which outline the preparation of chiral 3-hydroxy-2-oxindoles. One type of approach calls for the asymmetric nucleophilic addition of organometallic reagents[3] or electron-rich reagents[4–6] to isatins. The second approach entails asymmetric hydroxylation of 3-substituted 2-oxindoles.[7] Despite these developments, the available methodologies are often limited and a new methodology is highly desirable, considering the importance of chiral 3-substituted oxindoles. Scheme 1 Structure of SM-130686. Since the independent reports by Akiyama and Terada in 2004,[8] chiral phosphoric acids have proven to be versatile catalysts and have subsequently been applied to a variety of transformations with high stereocontrol.[9] Moreover, the alkali or alkaline earth derived salts of chiral phosphoric acids have proven to be highly effective catalysts in several recent reports.[10] Benzoyl peroxide (BPO) is a readily available oxylation reagent, which has been known for decades.[11] Nonetheless, asymmetric oxylation using BPO are very rare.[12] Herein, we describe, to the best of our knowledge, the first example of a highly enantioselective benzoyloxylation of an oxindole with BPO catalyzed by a chiral calcium phosphate (Scheme 2).[13] By comparison to published reports, this work provides access to 3-hydroxyoxindole derivatives with the highest stereoselectivity to date. Scheme 2 Enantioselective benzoyloxylation of oxindoles. We began our investigation with 3-phenyloxindole 1a and BPO as substrates, and toluene as the solvent, as a starting point for optimization studies. Chiral phosphoric acids purified by silica gel column chromatography, were then screened. Catalysts H[P1], H[P4], and H[P6] (Table 1, entries 1, 4, and 6) imparted meagre stereoselectivity. H[P6], a VAPOL-derived phosphoric acid, proved to be the best catalyst when TBME was the solvent (Table 1, entries 7– 9). The reverse selectivity was observed in DCM (Table 1, entry 10).[14] To our delight, an upgrade to 99% ee was obtained using diethyl ether (Table 1, entry 11). Interestingly, H[P6] washed with 6N HCl exhibited poor catalytic efficiency and enantioselectivity under the same conditions (Table 1, entry 12). Correlation of this result to that of a recent report by Ishihara and co-workers,[10a] showing a high abundance of chiral phosphate salts in the absence of a final HCl wash of the chiral phosphoric acid/salt mixture obtained by silica gel purification, directed us to propose the active catalytic species to be that of a chiral phosphate salt.[15] To identify the metal counterion, several variants of P6 were prepared and evaluated. Na[P6] and K[P6] afforded the product with no selectivity (Table 1, entries 13 and 14). Ca[P6]2 and Sr[P6]2 both induced remarkably high selectivity (>99%) (Table 1, entries 15 and 16). Ba[P6]2 allowed for a significantly lower enantioselectivity (7 %) (Table 1, entry 17). Mg[P6]2 furnished the product with 60% ee, but with the opposite configuration (Table 1, entry 18), presumably due to a difference on coordination spheres compared to calcium.[16] To our delight, excellent enantioselectivity (95%) is still observed with Ca[P6]2, even when the catalyst loading is reduced to 0.10 mol% (Table 1, entry 22). Table 1 Screening of catalysts and solvents.[a] With the optimized reaction conditions in hand, we turned our attention to the scope of the asymmetric benzoyloxylation of 3-aryloxindoles with Ca[P6]2. As shown in Table 2, introduction of either electron-donating or electron-withdrawing groups on the 3-aryl ring or the arene ring of the oxindole have little effect on the enantioselectivity (2a–2m). The majority of products were obtained with 99% ee and good yield. It is worthy of note that 3-aryloxindoles bearing a heteroatom can provide the desired product with excellent enantioselectivity (2n). Unfortunately, no product was detected using 3-benzyloxindole due to lower reactivity. Table 2 Substrate scope for the asymmetric benzoyloxylation of oxindoles.[a] Determination of the absolute configuration of the products, as well as potential synthetic utility of this methodology is shown in Scheme 3. Boc-deprotection followed by reduction of the benzoyl group of 2a yielded known compound 4a in two steps with good overall yield and excellent retention of chirality.[17] Scheme 3 Transformation of 2 a to known hydroxyoxindole 4 a. TFA = trifluoroacetic acid, DIBAL-H = diisobutylaluminum hydride. While a detailed mechanism for this novel transformation is unknown, we propose that the bifunctional nature of the chiral calcium phosphate salt allows for activation of both the nucleophile and the electrophile, as shown in Scheme 4. Two characteristics of calcium were considered in developing this plausible transition state. First, the low electronegativity of calcium should lead to a significant increase in the Bronsted basicity of the chiral phosphate counteranion. Second, calcium’s various coordination sites presumably allow for a greater number of favorable electrostatic interactions.[18] The coordination between calcium and the carbonyl oxygens of both BPO and the Boc-group of the oxindole serve not only to activate the electrophile but also force the two substrates to be in closer proximity to one another, in the chiral environment. These interactions coupled with the hydrogen-bonding interactions between the hydroxy group of the oxindole tautomer and the P=O moiety of the catalyst can be used to rationalize the unprecedented enantioselectivity observed. Scheme 4 Proposed transition state for the Ca[P6]2-catalyzed benzoyloxylation of oxindole 1 a. In conclusion, we report a novel asymmetric benzoyloxylation of 3-aryl-2-oxindoles catalyzed by a chiral VAPOL calcium phosphate salt. This transformation utilizes readily available benzoyl peroxide as a benzoyloxylation reagent. A series of 3-aryl-3-benzoyloxindoles are obtained with good yields and excellent enantioselectivities. Further studies of the benzoyloxylation of additional nucleophiles are currently under investigation in our laboratory and will be reported in due course.

Catalytic Asymmetric Addition of Alcohols to Imines: Enantioselective Preparation of Chiral N,O-Aminals

The enantioselective addition of alcohols to imine electrophiles has been shown to proceed in the presence of a catalytic amount of a chiral phosphoric acid catalyst. The reaction allows for the formation of the respective chiral N,O-aminals in excellent yield and enantioselectivity. A total of 11 different alcohols and 11 different imines were successfully used as a clear demonstration of the reaction generality.

Highly Enantioselective Hydrogenation of Enamides Catalyzed by Chiral Phosphoric Acids

A highly enantioselective hydrogenation of enamides catalyzed by a dual chiral-achiral acid system was developed. By employing a substoichiometric amount of a chiral phosphoric acid and acetic acid, catalyst loadings as low as 1 mol % of the chiral catalyst were sufficient to provide excellent yield and enantioselectivity of the reduction product.

An asymmetric Diels-Alder reaction catalyzed by chiral phosphate magnesium complexes: highly enantioselective synthesis of chiral spirooxindoles.

Mild Magic: A mild, enantioselective Diels-Alder reaction, catalyzed by a chiral magnesium phosphate species, has been developed for the synthesis of various chiral spirooxindoles. Molecular sieves were found to have a considerable effect when used as additives in this reaction.

Direct Synthesis of Chiral 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines via a Catalytic Asymmetric Intramolecular Aza-Friedel–Crafts Reaction

The direct asymmetric intramolecular aza-Friedel-Crafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with high yields and high enantioselectivities. This strategy has been shown to be quite general toward various aldehydes and pyrrole derivatives.

Brønsted Acid Catalyzed Asymmetric Propargylation of Aldehydes

Enantiomerically pure homopropargylic alcohols are highly useful intermediates, with broad synthetic utility. The terminal alkyne functionality serves as a synthetic handle for cross-coupling, metathesis, and heterocycle synthesis.[1] The addition of allenic or propargylic reagents to carbonyl compounds is mechanistically similar to the analogous reaction with allylic reagents. Though many useful and innovative methods exist for the synthesis of homoallylic alcohols,[2] the enantio-selective synthesis of homopropargylic alcohols remains arduous. Two main complications are 1) the lower reactivity of the allenylic and propargylic substrates in comparison to allylic substrates, and 2) the difficulties associated with controlling the reaction regioselectivity.[3] Herein, we describe a highly enantioselective catalytic method for the preparation of homopropargylic alcohols. Computational studies of the reaction provide insight into the catalysis and stereochemistry of the reaction. Many current methods for enantioselective propargylation reactions rely upon the use of chiral reagents.[4] Alternative catalytic methods have been developed, but are limited to the use of allenylic or propargylic metal-based reagents or intermediates.[2a,5] Despite notable work, many of these methods are restricted by one or more limitations. Among them are 1) the use of reagents that are relatively difficult to prepare or are unstable to air and/or moisture, 2) the use of undesirable metal reagents or catalysts, and 3) regioselectivity concerns. In the past decade, Lewis and Bronsted acid-catalyzed allylboration reactions have fascinated the synthetic community.[6,7] However, this methodology remains relatively undeveloped for the more challenging allenylboration of aldehydes. Following our recent report on the development of a chiral phosphoric acid-catalyzed allylboration,[7] we examined the extension of our methodology to the enantioselective propargylation of aldehydes. We began our investigation with the reaction of benzaldehyde and allenyl boronic acid pinacol ester. Boronate 2 is a relatively stable, non-toxic and commercially available reagent. The C–C bond formation proceeded smoothly in the presence of various chiral acid catalysts,[8] with complete control over the regioselectivity (Table 1). PA5[9] afforded product 3 with the highest enantio-selectivity, when toluene was used as the reaction solvent. An increase to 87% ee was seen with the use of higher catalyst loading, in the presence of 4A M.S. (entry 13). The enantio-selectivity could be further increased, when the reaction was conducted at lower reaction temperatures of 0°C (entry 14) and −20°C (entry 15), albeit with longer reaction times. Table 1 Catalyst screening and optimization for the propargylation of benzaldehyde.[a] With the optimized conditions in hand,[10] a variety of aldehydes with different electronic and steric properties were tested to study the scope and limitation of the developed methodology (Table 2). The reaction proved tolerant to electron-donating and electron-withdrawing groups (1a–1j), giving excellent yields and enantioselectivities (92–96% ee). The methodology was extended to aliphatic aldehydes (1k–1m), furnishing the corresponding homopropargylic alcohol products 3k–m in 77–82% ee. Table 2 Enantioselective propargylation of aldehydes.[a] We prepared several important synthetic scaffolds, previously unavailable from enantioenriched homopropargylic alcohols (Scheme 1). Chiral dihydrofuran-3-ones, such as 4, are important building blocks[11] for the synthesis of biologically active compounds. Despite their importance, a general enantioselective synthesis for this class of molecule has yet to be reported. We successfully transformed 3a[12] into dihydrofuran-3-one 4, by employing gold-catalyzed reaction methodology developed by Zhang and co-workers,[13] with complete preservation of the enantiomeric excess. Crabbe homologation of 3a provided optically active 3,4-allenol 5, which has the potential to serve as a substrate in natural product synthesis.[14] Chiral dihydrofuran 6, currently dependent on the Heck reaction for its synthesis,[15] was obtained through a molybdenum-mediated cycloisomerization of 3a, based on methodology developed by McDonald and co-workers.[16] Scheme 1 Synthesis of important chiral moieties. It is our belief that the propargylation proceeds through a six-membered cyclic transition state, where catalyst activation operates by hydrogen-bonding of the boronate oxygen. To further understand the mechanism and stereoselectivity of this phosphoric acid-catalyzed propargylation reaction, we performed theoretical calculations. Calculated energies of different pathways for allylboration[17] and propargylation showed that Bronsted acids form a strong hydrogen bond with the pseudo-equatorial oxygen of the allenyl boronate.[18] A computed transition state structure involving protonation is shown in Figure 1. Figure 1 Transition state structure for the Bronsted acid-catalyzed propargylation reaction. To explore the origins of the enantioselectivity, we studied the transition state structures for the propargylation reaction, where the phosphoric acid catalyst activates the pseudo-equatorial oxygen of the allenyl boronate. Biphenol(bipol)-derived phosphoric acid was used as the model, in place of the fully derived binol phosphoric acid, to reduce the computational time. Catalyst PA5, bearing a 2,4,6-triisopropylphenyl group at the 3,3′-positions, provides high experimental enantioselectivity. Thus, the diastereomeric transition states of the re-face and si-face attack involving the bipol model of PA5 were compared. Transition states TSr1 and TSs1 are represented in Figure 2. Re-face attack (TSr1) is predicted to be more favored than si-face attack (TSs1) by 1.3 kcalmol−1. This is in agreement with the 74% ee obtained experimentally. Figure 2 Optimized structures of TSr1 and TSs1. Relative energies (kcal mol−1) are shown in parentheses. Figure 2 shows a lack of obvious steric differences in the transition states. H–H distances are 2.4 A or more. However, the distortion of the catalyst is larger in TSs1 than in TSr1 by about 1.2 kcalmol−1. This distortion relieves steric repulsions that would otherwise occur. The preference for re-facial selectivity is therefore the result of the larger distortion of the catalyst–boronate complex in TSs1. The origins of the differences in distortion energies of the catalyst–boronate complex in the two TSs can be visualized from geometries of the catalyst in the TSs. Figure 3a shows the catalyst–boronate complex structure in TSr1. Here, the dioxaborolane ring has no significant steric interaction with the catalyst, and the dihedral angle between the 2,4,6-triisopropylphenyl substituent and the bipol core is 74°, almost the same as the dihedral angle of 72° in the optimized catalyst. Figure 3b shows the catalyst–boronate complex structure in TSs1, with the dioxaborolane ring on the left. The methyl groups (circled in Figure 3b) of the dioxaborolane ring and the isopropyl groups of the catalyst (circled in Figure 3b) are close to each other. In order to minimize such steric repulsions, the 2,4,6-triisopropylphenyl substituent is rotated around the bond to the bipol phenyl core with a dihedral angle of 78°. This is a 6° rotation away from the dihedral angle in the optimized catalyst (72°). The asymmetric induction can be rationalized by differences in distortion energies originating from the steric interactions between the substrates and the bulky 3,3′-substituents on the catalyst. Figure 3 a) 3D structure of TSr1 without benzaldehyde. b) 3D structure of TSs1 without benzaldehyde. For other catalysts screened experimentally, calculations showed the absence of an energy difference between re- and si-attack diastereomeric transition states, suggesting why these catalysts gave low enantioselectivities. In summary, we have developed the first Bronsted acid-catalyzed propargylation of aldehydes, for the synthesis of chiral homopropargylic alcohols. The reaction is simple and highly efficient, demonstrating broad synthetic utility. Mechanistic studies show the catalyst activating the reaction by forming a strong hydrogen bond with the pseudo-equatorial oxygen of the boronate. The high enantioselectivity obtained with catalyst PA5 originates from steric interactions between the methyl groups of the allenylboronate, the bulky catalyst substituents, and the resulting distortion of the catalyst.

Chiral Phosphoric Acid-Catalyzed Desymmetrization of meso-Aziridines with Functionalized Mercaptans

Conditions for the phosphoric acid-catalyzed highly enantioselective ring-opening of meso-aziridines with a series of functionalized aromatic thiol nucleophiles are described. The procedure utilizes commercially available aromatic thiols, a series of meso-aziridines, and a catalytic amount of VAPOL phosphoric acid to explore the substrate scope of this highly enantioselective reaction.

Chiral Magnesium BINOL Phosphate-Catalyzed Phosphination of Imines: Access to Enantioenriched α-Amino Phosphine Oxides

A new method to synthesize chiral α-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine oxide and is catalyzed by a chiral magnesium phosphate salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.