Boronic Acid/Palladium Hybrid Catalysis for Regioselective O-Allylation of Carbohydrates.

Novel imidazole-containing boronic acid and palladium hybrid catalysis for regioselective O-allylation of carbohydrates has been developed. This catalytic process enables the introduction of a useful allyl functional group into the equatorial hydroxy group of cis-1,2-diols of various carbohydrates with low catalyst loading and excellent regioselectivities. This is the first report on hybrid catalysis in combination with a Lewis base-containing boronic acid and a transition metal complex.

Concise Synthesis of 2,5-Diketopiperazines via Catalytic Hydroxy-Directed Peptide Bond Formations.

2,5-Diketopiperazines (DKPs) with hydroxymethyl functional groups are essential structures found in many bioactive molecules and functional materials. We have established a simple protocol for the concise synthesis of this type of DKPs through diboronic acid anhydride-catalyzed hydroxy-directed peptide bond formations. The sequential reactions in this report, which consist of three steps, an intermolecular catalytic condensation reaction in which water is the only byproduct, a simple deprotection of the nitrogen-protecting group, and an intramolecular cyclization, enabled the synthesis of functionalized DKPs in high to excellent yields without any intermediate purification. The utility of this protocol has been demonstrated by synthesizing natural products, phomamide and Cyclo(Deala-l-Leu).

Boronic Acid-Catalyzed Regioselective Koenigs-Knorr-Type Glycosylation.

Boronic acid-catalyzed regioselective Koenigs-Knorr-type glycosylation is presented. The reaction of an unprotected or partially protected glycosyl acceptor with a glycosyl halide donor in the presence of silver oxide and a low catalytic amount of imidazole-containing boronic acid was found to proceed smoothly, which enables construction of a 1,2-trans glycosidic linkage with high regioselectivities. This is the first example of the use of a boronic acid catalyst to initiate regioselective glycosylation via the activation of cis-vicinal diols in glycosyl acceptors.

Boronic Acid-Catalyzed Final-Stage Site-Selective Acylation for the Total Syntheses of O-3'-Acyl Bisabolol ß-D-Fucopyranoside Natural Products and Their Analogues.

The first concise total syntheses of O-3'-senecioyl α-bisabolol ß-D-fucopyranoside (4a) and O-3'-isovaleroyl α-bisabolol ß-D-fucopyranoside (4b) were achieved through final-stage site-selective acylation via the activation of cis-vicinal diols by imidazole-containing boronic acid catalysts as a key step. This synthetic method was also effective for the syntheses of unnatural analogues with modified acyl side chains or carbohydrate moiety.

Total syntheses of seminolipid and its analogues by using 2,6-bis(trifluoromethyl)phenylboronic acid as protective reagent.

A concise total synthesis of seminolipid, a sulfoglycolipid, has been achieved; key features include regioselective, tin-free sulfation of allyl ß-d-galactopyranoside using 2,6-bis(trifluoromethyl)phenylboronic acid as protective reagent, stereoselective epoxidation, and site-selective acylation. The utility of this divergent synthetic approach to introduce 2,2,2-trichloroethyl-protected sulfate group at an early stage without toxic and environmentally unfavorable tin reagents was demonstrated by the syntheses of three seminolipid analogues with different side-chains from the common intermediate.

C1'-Azacycloalkyl Hexahydrocannabinols.

We report the design, synthesis, and biological evaluation of a novel class of cannabinergic ligands, namely C1'-azacycloalkyl hexahydrocannabinols. Our synthetic approaches utilize an advanced common chiral intermediate triflate from which all analogues could be derived. Key synthetic steps involve microwave-assisted Liebeskind-Srogl C-C cross-coupling and palladium-catalyzed decarboxylative coupling reactions. The C1'-N-methylazetidinyl and C1'-N-methylpyrrolidinyl analogues were found to be high affinity ligands for the CB1 and CB2 cannabinoid receptors.

Asymmetric Total Synthesis of (-)-Englerin A through Catalytic Diastereo- and Enantioselective Carbonyl Ylide Cycloaddition.

An asymmetric total synthesis of the guaiane sesquiterpene (-)-englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo- and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], [Rh2 (S-TCPTTL)4 ], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo-face. Another notable feature of the synthesis is ruthenium tetraoxide-catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.

Enantioselective palladium(0)-catalyzed Nazarov-type cyclization.

A Pd(0)-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity. It is noteworthy that the reaction does not require that substrates should be activated by aryl substituents.

Hydroxy-directed peptide bond formation from α-amino acid-derived inert esters enabled by boronic acid catalysis.

A boronic acid-catalyzed peptide bond formation from α-amino acid methyl esters is described. The catalysis showed high chemoselectivity for ß-hydroxy-α-amino esters, affording the peptides in high to excellent yields with high functional group tolerance. This hydroxy-directed peptide bond formation could be applicable to oligopeptide syntheses. This is the first successful example of organoboron-catalyzed peptide bond formation from α-amino acid-derived inert esters.

Organoboron catalysis for direct amide/peptide bond formation.

Amides and peptides are ubiquitous functional groups found in several natural and artificial materials, and they are essential for the advancement of life and material sciences. In particular, their relevance in clinical medicine and drug discovery has increased in recent years. Dehydrative condensation of readily available carboxylic acids with amines is the most "direct" method for amide synthesis; however, this methodology generally requires a stoichiometric amount of condensation agent (coupling reagent). Catalytic direct dehydrative amidation has become an "ideal" methodology for synthesizing amides from the perspective of green chemistry, with water as the only byproduct in principle, high atom efficiency, environmentally friendly, energy saving, and safety. Conversely, organoboron compounds, such as boronic acids, which are widely used in various industries as coupling reagents for Suzuki-Miyaura cross-coupling reactions or pharmaceutical structures, are environmentally friendly molecules that have low toxicity and are easy to handle. Based on the chemical properties of organoboron compounds, they have potential Lewis acidity and the ability to form reversible covalent bonds with dehydration, making them attractive as catalysts. This review explores studies on the development of direct dehydrative amide/peptide bond formation reactions from carboxylic acids using organoboron catalysis, classifying them based on chemical bonding and catalysis over approximately 25 years, from the early developmental days to 2023.

Catalytic dehydrative amide bond formation using aqueous ammonia: synthesis of primary amides utilizing diboronic acid anhydride catalysis.

Although aqueous ammonia is an inexpensive and readily available safe source of ammonia, there have been no successful studies on direct catalytic dehydrative amidations of carboxylic acids with aqueous ammonia. In this study, we report a catalytic methodology for the synthesis of primary amides through diboronic acid anhydride (DBAA)-catalyzed dehydrative condensation of carboxylic acids with aqueous ammonia as the amine substrate.

An organocatalytic asymmetric Nazarov cyclization.

An organocatalytic asymmetric Nazarov cyclization of diketoesters that proceeds by means of a dual activation mechanism has been developed. Screening of a number of catalysts led to a new thiourea that incorporates a primary amino group. The method gives rise to cyclic products with two adjacent quaternary asymmetric carbon atoms, one of which is an all-carbon stereocenter, with complete or nearly complete diastereoselectivity and in high or very high enantiomeric excess. A brief and very convenient synthesis of the acyclic diketoester starting materials through nucleophilic addition to a ketene is also described.

Catalytic asymmetric synthesis of the endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product from Ligusticum chuanxing via 1,3-dipolar cycloaddition of a formyl-derived carbonyl ylide using Rh2(S-TCPTTL)4.

The reaction of a six-membered cyclic formyl-carbonyl ylide derived from alpha-diazo-beta-ketoester with phenylacetylene derivatives under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh(2)(S-TCPTTL)(4), provides cycloadducts containing an 8-oxabicyclo[3.2.1]octane ring system in up to 97% ee. This represents the first example of an enantioselective 1,3-dipolar cycloaddition of a cyclic formyl-carbonyl ylide. Using this catalytic process, an asymmetric synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product 1 from Ligusticum chuanxing Hort. has been achieved.

Diboronic Acid Anhydride-Catalyzed Direct Peptide Bond Formation Enabled by Hydroxy-Directed Dehydrative Condensation.

We report the catalytic direct peptide bond formations via dehydrative condensation of ß-hydroxy-α-amino acids, affording the serine, threonine, or ß-hydroxyvaline-derived peptides in high to excellent yields with high functional group tolerance, minimum epimerization, and excellent chemoselectivity. The key to the success of these atom-economical transformations is the use of diboronic acid anhydride catalyst for the hydroxy-directed reactions.

Synthesis of Weinreb amides using diboronic acid anhydride-catalyzed dehydrative amidation of carboxylic acids.

The first successful example of the direct synthesis of Weinreb amides using catalytic hydroxy-directed dehydrative amidation of carboxylic acids using the diboronic acid anhydride catalyst is described. The methodology is applicable to the concise syntheses of eight α-hydroxyketone natural products, namely, sattabacin, 4-hydroxy sattabacin, kurasoins A and B, soraphinols A and B, and circumcins B and C.

Catalytic Activation of Cis-Vicinal Diols by Boronic Acids: Site-Selective Acylation of Carbohydrates.

Site-selective acylation of unprotected carbohydrates by using stable, storable, and easily handled imidazole-containing organoboronic acid catalysts is described. This catalytic process with low catalyst loading enables the introduction of a wide variety of acyl functional groups into the equatorial position of cis-vicinal diols in unprotected hexapyranosides with excellent site selectivity. This is the first example that uses a Lewis base-containing boronic acid to enhance the nucleophilicity of hydroxy groups.

Diboronic Acid Anhydrides as Effective Catalysts for the Hydroxy-Directed Dehydrative Amidation of Carboxylic Acids.

The direct catalytic dehydrative amidation of ß-hydroxycarboxylic acids with amines is described. A biphenyl-based diboronic acid anhydride with a B-O-B skeleton is shown to be an exceptionally effective catalyst for the reaction, providing ß-hydroxycarboxylic amides in high to excellent yields with a low catalyst loading (minimum of 0.01 mol %, TON up to 7,500). This hydroxy-directed amidation shows excellent chemoselectivity and is applicable to gram-scale drug synthesis.

2,6-Bis(trifluoromethyl)phenylboronic Esters as Protective Groups for Diols: A Protection/Deprotection Protocol for Use under Mild Conditions.

The application of 2,6-bis(trifluoromethyl)phenyl boronic acid ( o-FXylB(OH)2; o-FXyl = 2,6-(CF3)2C6H3) as a recoverable and reusable protective agent for diols is described. The resulting cyclic boronic esters are water- and air-stable and tolerant to various organic transformations. Moreover, they can be deprotected under mild conditions. This methodology was applied to the synthesis of a highly conjugated enetriyne natural product with anti-angiogenic activities.