N-Methylated Peptide Synthesis via Generation of an Acyl N-Methylimidazolium Cation Accelerated by a Brønsted Acid

The development of a robust amide-bond formation remains a critical aspect of N-methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N-methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N-methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate-limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.     

O-Benzenedisulfonimide as a Reusable Brønsted Acid Catalyst for Hetero-Michael Reactions

The hetero-Michael reactions among various oxygen, sulfur, and nitrogen nucleophiles and α,β-unsaturated compounds were carried out in the presence of catalytic amounts of o-benzenedisulfonimide as Brønsted acid organocatalyst. The reaction conditions were very mild, and the yields of target products were good. The catalyst was easily recovered and purified, ready to be used in further reactions. This ability grants economic and ecological advantages.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Highly Enantioselective Brønsted Acid Catalyzed Heyns Rearrangement

Herein we report the first method for highly enantioselective Brønsted acid catalyzed Heyns rearrangements. These reactions, catalyzed by a chiral spiro phosphoric acid, afforded synthetically valuable chiral α-aryl-α-aminoketones which cannot be obtained by means of previously reported Heyns rearrangement methods. This method features low catalyst loadings, high yields and high enantioselectivities, making these reactions highly practical. We used the method to efficiently synthesize various chiral amines, including some biologically active molecules. We experimentally proved that these acid-catalyzed Heyns rearrangements proceeded via a proton-transfer process involving an enol intermediate and the stereocontrol was realized during the proton-transfer step.     

Brønsted Acid and H-Bond Activation in Boronic Acid Catalysis

Boronic acid catalysis has emerged as a mild method for promoting a wide variety of reactions. It has been proposed that the mode of catalysis involves Lewis acid or covalent activation of hydroxyl groups by boron, but limited mechanistic evidence exists. In this work, representative boronic acid catalyzed reactions of alcohols and oximes have been reinvestigated. A series of control experiments with boronic and Brønsted acids were interpreted along with correlations between their reactivity and their acidity measured by the Gutmann–Beckett method. Overall, it was concluded that the major modes of catalysis involve either dual H-bond catalysis or Brønsted acid catalysis. Strong Brønsted acids were shown to be generated in situ from covalent assembly of the boronic acids with hexafluoroisopropanol, explaining why the solvent had such a major impact on the reactivity. This new insight should guide the future development of boronic acid catalysis, where the diverse and solvent-specific nature of catalytic modes has been overlooked.     

Brønsted Acid Catalyzed Asymmetric Synthesis of cis-Tetrahydrocannabinoids**

We report herein the catalytic asymmetric cyclization of 1-aryl terpenols to afford enantiomerically highly enriched Δ⁹-cis-tetrahydrocannabinoid scaffolds in a single step. As powerful chiral catalysts strongly acidic imidodiphosphorimidates (IDPis) have been identified which furnish the products with good yields and excellent enantioselectivity. Upon MOM-deprotection some naturally occurring cannabimimetica such as (−)-cis-Δ⁹-tetrahydrocannabinol and (−)-perrottetinene as well as some unnatural analogues were made accessible along a merely 3-step biomimetic sequence (MOM=methoxymethyl).     

Relationship between the Brønsted Coefficients of the Steps of a Heterogeneous Catalytic Reaction

Kinetics and Catalysis - The thermodynamics of the catalytic cycle under the influence of the reaction medium on the catalyst was considered. The change in the activation energy of the reaction...     

Brønsted Acid Promoted Sulfonylation of Propargylic Alcohols: Synthesis of Triaryl Allenyl Sulfones under Mild Conditions

An efficient and practical approach for the synthesis of triaryl allenyl sulfones from easily accessible propargylic alcohols was developed, by using sodium sulfinates as a sulfonyl source in the presence of Brønsted acid. The reaction proceeded via allenyl carbocation as the key intermediate and was followed by a nucleophilic attack of sodium sulfinates to produce allenyl sulfones in moderate to excellent yields.     

Brønsted acid-catalyzed imine amidation

A new method for the Br?nsted acid-catalyzed addition of amide nucleophiles to imines to produce protected aminal products is described. Simple Br?nsted acids (phenyl phosphinic acid and trifluoromethanesulfonimide) were shown to be excellent catalysts, providing high yields of the aminal product. A catalytic asymmetric imine amidation using sulfonamides as nucleophiles was successful when a hindered biaryl phosphoric acid catalyst derived from 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol (VAPOL) was used. Excellent yields and enantioselectivities were found in these additions (up to 99% ee).     

Super Brønsted acid catalysis

Br?nsted acid catalysis has emerged as a new class of catalysis in modern organic synthesis. However, in order to make the utility of the Br?nsted acid catalysis as broad as the well-developed Lewis acid catalysis, it is desirable to develop Br?nsted acids demonstrating both high reactivities and selectivities. In this feature article, we will present our achievement in the design and development of strong Br?nsted acids and their application to organic reactions. Furthermore, we will describe the Tf(2)NH-catalyzed Mukaiyama aldol reaction of super silyl enol ethers. We also will highlight the differences in reactivity and chemo- and stereo-selectivity between Br?nsted and Lewis acid catalysis.     

Enantioselective Synthesis of Tropanes: Brønsted Acid Catalyzed Pseudotransannular Desymmetrization

The enantioselective synthesis of tropanols has been accomplished through chiral phosphoric acid catalyzed pseudotransannular ring opening of 1-aminocyclohept-4-ene-derived epoxides. The reaction proceeds together with the desymmetrization of the starting material and leads to the direct formation of the 8-azabicyclo[3.2.1]octane scaffold with excellent stereoselectivity. The synthetic applicability of the reaction was demonstrated by the enantioselective synthesis of the two natural products (−)-α-tropanol and (+)-ferruginine.     

Design of Brønsted acid-assisted chiral Brønsted acid catalyst bearing a bis(triflyl)methyl group for a Mannich-type reaction

[Structure: see text] A new Br?nsted acid-assisted chiral Br?nsted (chiral BBA) acid catalyst (1) was developed by substituting a hydroxy group of optically active 1,1'-bi(2-naphthol) with a stronger Br?nsted acidic group such as a bis(trifluoromethanesulfonyl)methyl group. The enantioselective Mannich-type reaction of ketene silyl acetals with aldimines catalyzed by (R)-1 in the presence of stoichiometric achiral proton sources gave (S)-beta-amino esters in high yield with moderate to good enantiomeric excesses.     

Generation of a solid Brønsted acid site in a chiral framework

Protonation of chiral porous materials introduces a Br?nsted acid centre, the structure of which is unique to the heterogeneous phase requiring pore wall confinement for stable isolation.     

Asymmetric Aza-Diels–Alder Reaction with Ion-Paired—Iron Lewis Acid—Brønsted Acid Catalyst

The development and use of a multiple-activation catalyst with ion-paired Lewis acid and Brønsted acid in an asymmetric aza-Diels–Alder reaction of simple dienes (non-Danishefsky-type electron-rich dienes) was achieved by utilizing the [FeBr₂]⁺[FeBr₄]⁻ combination prepared in situ from FeBr₃ and chiral phosphoric acid. Synergistic effects of the highly active ion-paired Lewis acid [FeBr₂]⁺[FeBr₄]⁻ and a chiral Brønsted acid are important for promoting the reaction with high turnover frequency and high enantioselectivity. The multiple-activation catalyst system was confirmed using synchrotron-based X-ray absorption fine structure measurements, and theoretical studies. This study reveals that the developed catalyst promoted the reaction not only by the interaction offered by the ion-paired Lewis acid and the Brønsted acid but also noncovalent interactions.     

Directing-Group-Free C7-Alkylations of N-Alkylindoles Mediated by Cationic Zirconium Complexes: Role of Brønsted Acid for Catalytic Manifold

Highly position selective alkylations of N-alkylindoles at C7-positions have been enabled by cationic zirconium complexes. The strategy provides a straightforward access to install alkyl groups at C7-positions of indoles without a complex directing group. Mechanistic studies provided support for the importance of Brønsted acids in the catalytic manifold.     

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.     

Efficient Synthesis of bis- and tris-Indolylalkanes Catalyzed by a Brønsted Acid–Surfactant Catalyst in Water

A simple and efficient synthesis of bis- and tris-indolylalkanes from carbonyls (aldehydes/ketones) and indoles with excellent yields in the presence of dodecylsulphonic acid (DSA) in water at room temperature is described. The catalyst is also applicable for the synthesis of 3,3-di(3-indolyl)oxindoles. The dodecylsulphonic acid acts as both Brønsted acid and surface-active agent in the reaction mixture.     

Brønsted Acid-Catalyzed Enantioselective Cycloisomerization of Arylalkynes

The first example of an enantioselective carbocyclization of an alkyne-containing substrate catalyzed by chiral Brønsted acids was achieved. The use of the 2-hydroxynaphthyl substituent on the alkyne as a directing group constituted the key parameter enabling both efficient regioselective protonation of the carbon–carbon triple bond and chiral induction. The key cationic intermediate could be depicted either as a cationic vinylidene ortho-quinone methide or a stabilized vinyl cation. Atropoisomeric phenanthrenes derivatives were produced in high yields and good enantioselectivities under mild, metal-free reaction conditions in the presence of chiral N-triflylphosphoramide catalysts. The carbenic nature of the cationic intermediate was also exploited to describe an example of alkyne/alkane cycloisomerization.