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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.

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).

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.

We report the catalytic direct peptide bond formations via dehydrative condensation of β-hydroxy-α-amino acids, affording the serine, threonine, or β-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.

The direct catalytic dehydrative amidation of β-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 β-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.

A functional polymorphism in methylenetetrahydrofolate reductase (MTHFR) has been identified at codon 677 (C677T). The T-allele variant (valine type) has lower enzyme activity than the wild type (C-allele or alanine type), resulting in a slightly elevated homocysteine level, which has been recently recognized as a risk factor for fracture. However, whether subjects bearing the T allele have higher susceptibility to fractures is still controversial. We have investigated the effects of MTHFR polymorphism on fracture susceptibility in Japanese postmenopausal women. A total of 502 postmenopausal ambulatory Japanese women were followed up for 5.1 +/- 3.4 (mean +/- SD) years, and a total of 155 patients with incident fractures (121 patients with vertebral fractures and 34 cases with fractures at other sites) were recorded. When compared with the patients without any fractures, the patients with incident fractures were older, had more prevalent fractures, had higher urinary levels of bone turnover markers as well as plasma homocysteine level, but were shorter in body height and had lower bone mineral density. The prevalence of the TT genotype of MTHFR was significantly higher in the patients with incident fractures compared to the other genotypes. The subjects with the TT genotype had a higher incidence rate of fracture and higher plasma level of homocysteine than the subjects bearing the non-TT genotype. This relationship was observed in both osteoporotic and nonosteoporotic groups. The hazard ratio for TT genotype without osteoporosis, non-TT genotype with osteoporosis, and TT genotype with osteoporosis was 1.49 (0.91-2.45), 3.64 (2.50-5.29), and 7.21 (4.34-11.97), respectively, compared to the non-TT genotype without osteoporosis. A higher hazard ratio for the TT genotype with osteoporosis was still apparent after adjustment for age, body size, and number of prevalent vertebral fractures. These results indicate that the TT genotype of MTHFR may be a risk factor for future fracture in addition to the traditional risk factors.

To clarify the involvement of perilipin, a lipid-droplet-surface protein associated with adipocytes and steroidogenic cells, in the differentiation of sebocytes, we investigated the expression of perilipin in sebaceous glands in vivo and in vitro. Perilipin was expressed in sebaceous glands of the hamster auricle in vivo and was localized at the surface of intracellular lipid droplets in differentiated hamster sebocytes in vitro. Western blot analysis showed that perilipin with a molecular weight of approximately 57 kDa, which was identical to that in differentiated mouse 3T3-L1 adipocytes, was detected in cultured sebocytes, indicating that sebaceous glands expressed perilipin A. In addition, the production of perilipin A in cultured sebocytes was transcriptionally augmented by sebocytic-lipogenesis stimulators, insulin, and 5alpha-dihydrotestosterone, whereas it was decreased by a suppressor of sebocytic differentiation, epidermal growth factor. Furthermore, hamster sebocytes were found to express peroxisome proliferation-activating receptor alpha and gamma1, the activation of which by WY14643 and troglitazone, respectively, caused the transcriptional augmentation of perilipin A expression along with an increase in levels of triacylglycerols in lipid droplets in sebocytes. Therefore, these results provide novel evidence that the expression of perilipin A increases on the surface of intracellular lipid droplets augmented along with the differentiation of hamster sebocytes.