A overview of recent studies on remote asymmetric induction using chiral sulfoxides, with ca. 30 references i.e., a) reductions of sulfinyl ketones, b) C-O bond fission reactions of sulfinyl bicyclic acetals, c) Mukaiyama aldol condensations of sulfinyl aldehydes, and d) hetero Diels-Alder reactions and Diels-Alder reactions of sulfinyl dienophiles, is described. The role of the sulfinyl auxiliary and the Lewis acid, and the stereoselectivities are also analyzed.
A palladium complex coordinated by an iminophosphine ligand was disclosed to be a remarkably active catalyst for the coupling of organostannanes with aryl halides. The mechanistic studies show that the reaction of an alkynylstannane proceeds through a novel catalytic cycle which involves an oxidative addition of the organostannane to a Pd (0) -iminophosphine complex. This oxidative adduct was demonstrated to react with alkynes to give carbostannylation products. The catalyst could also mediate the homocoupling reaction of organostannanes using air or allyl acetate as a mild and easily available oxidant.
The use of palladium complexes as reagents for the synthesis of biologically active natural products has been under development for at least the past three decades, and many elegant total syntheses of structurally complicated natural products, possessing pharmacologically important properties, have been realized employing Heck reaction, cycloisomerization process, and allylic alkylation reaction. In our recent contribution to this area, we would like to describe total syntheses of aphidicolin (diterpene), pumiliotoxin C (alkaloid), methyl pederate (left segment of mycalamides), hirsutene (sesquiterpene), stemodin (diterpene), and methyl atis-16-en-19-oate (diterpene) using palladium-promoted cyclization as key step. Although the palladium-promoted cycloalkenylation reaction of an olefinic silyl enol ether is a powerful strategy for construction of polycyclic system, relatively little is known about successful application of the above reaction to biologically active natural product syntheses. Herein we report the development of novel palladium-catalyzed cycloalkenylation reaction of cross-conjugated silyl enol ethers and its application to a tetracyclic diterpene synthesis.
For the development of new receptor molecules that can precisely recognize sugar molecules, we synthesized a number of diboronic acids. Since one boronic acid can react with two OH groups (one diol group) to form a boronate ester, one diboronic acid can immobilize two diol units to form a sugarcontaining macrocycle. The selectivity can be tuned by the relative spatial position of the two boronic acids and the complexation event can be read out by circular dichroism, UV-Vis, and fluorescence spectroscopy. The nature presents a variety of saccharide structures to us which are already utilized as a “recognition tag” or a “supramolecular building-blocks” in the life processes. If we gain some efficient interfaces to control chemical and physical properties of saccharides, it will become possible to mimic this chemistry in artificial systems. As a research target to challenge this new concept, we can now raise three examples which are currently studied in our laboratory.
Practical and highly stereoselective aryl and allyl C-glycosidations using unprotected sugars as glycosyl donors have been developed. Aryl C-glycosidations of several unprotected 2-deoxy sugars with phenol and naphthol derivatives by the combined use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) -AgClO4 or TMSOTf exclusively gave the corresponding unprotected ο-hydroxyaryl β-C-glycosides which appear in many biologically attractive aryl C-glycoside antibiotics as the key subunit. On the other hand, allyl C-glycosidations of several unprotected glycals with allyltrimethylsilane by TMSOTf afforded the corresponding unprotected and 2, 3-unsaturated allyl α-C-glycosides in high yields which are versatile synthetic intermediates for the syntheses of optically active natural products. Furthermore, the total synthesis of urdamycinone B, a prototypical member of the C-glycosyl angucycline antibiotics, was accomplished by the successful application of the present aryl C-glycosidation of unprotected sugar as the key step.
Gastrointestinal motility dysfunctions entailed in non ulcer dyspepsia, gastroparesis and reflex oesophagitis are known to be effectively treated with the gastroprokinetic agents e.g. metoclopramide and cisapride. The mechanism of gastroprokinetic action is accepted to be correlated with agonistic activity at 5-HT4 receptor. Metoclopramide and cisapride concurrently have dopamine D2 receptor antagonistic activity, which is responsible for unfavorable side effects such as extrapyramidal symptoms and central nervous system depression. To obtain gastroprokinetic agents with more potent and selective than metoclopramide, 4-amino-N- [(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-methoxy-benzamide was designed and prepared. As a result of structure-activity relationship studies, mosapride was identified as a novel gastroprokinetic agent. As an extension of this project, the N- (1-benzyl-4- methylhexahydro-1, 4-diazepin-6-yl) benzamides and carboxamides were evaluated for 5-HT3 receptor antagonistic activity, and DAT-582 was selected as an optimal compound. DAT-582 was exhibited to be highly effective for the blockade of chemotherapy-induced nausea and emesis.
A novel synthesis of methyl 6-acetylsalicylate, a key intermediate directed at 6-substituted pyrimidin-2-yl-salicylate herbicides (PS) and their analogues, was studied. Three synthetic approaches were successful. Among them, a regioselective ortholithiation method was the most promising, and was applied for the synthesis of various 6-acylsalicylates and for the commercial synthetic method of Pyriminobac-methyl as well. Using methyl 6-acylsalicylate, 6-acyl pyrimidin-2-yl-salicylates (6-acyl PS), their acetal analogues and the close related phthalide analogues were synthesized and their herbicidal activities were evaluated. Among them, the compounds such as methyl 2-acetyl-6- [(4, 6- dimethoxypyrimidin-2-yl) oxy] benzoate gave excellent control of barnyard grass, but had unacceptable injury against rice. In order to reduce rice crop injury while keeping herbicidal activity, further extensive synthetic modification of 6-acyl PS was then examined by the introduction of an oximino group. QSAR study was carried out by examining their herbicidal activity against barnyard grass in paddy rice at various growth stages, including pre-emergence. Finally, Pyriminobac-methyl was found to be the most promising candidate and the industrial synthetic scheme was accomplished by modification of the regioselective ortholithiation method. Recently, Pyriminobac-methyl (Prosper®) was developed for the commercial herbicide and launched to the market.