A copper catalyst generates various reactive carbon species, which are useful reagents for organic synthesis. Among them, radical species are one of the most powerful tools to synthesize complex molecules. The reaction of α-bromocarbonyl compounds (Br-CRR’COR”) and Cu(I) salts possessing a multi-dentate nitrogen ligand generates alkyl radicals (·CRR’COR”). Although this reaction system has been well studied in radical additions and polymerizations, the development of diverse reaction modes by using the combination of olefins and α-bromocarbonyl compounds in the presence of a copper catalyst and excess base has not yet been explored. During the course of our study, we found that the resulting radical species show unique reactivities for olefins: 1) Mizoroki-Heck like olefinations of styrenes and α-bromocarbonyl compounds to give tertiary-alkyl substituted styrenes under Cu-PMDETA catalyst system, 2) distal-selective olefinations of α-alkylstyrenes and α-bromocarbonyl compounds under Cu-TPMA catalyst system, 3) formal [2+1] cycloadditions of styrenes and 2-bromomalonates to give donor-acceptor cyclopropanes, and 4) formal [3+2] cycloaddition of styrenes and 2-bromoketoesters to give dihydrofurans, which is very effective to synthesize all different aryl-substituted furans. Those reactions can be accomplished by the combination of a radical reaction and a polar reaction including an elimination with a base, and a nucleophilic reaction of an enolate.
Our cyclizations and ring transformations via two types of spirocyclic arenium ions are described in this article. A spiro [5.2] octadienyl cation, which is well known as a Cram’s arenium ion, has attracted considerable attention in the aspect from physical organic chemistry. Our effort to utilize the intermediate as a synthetic tool resulted in the development of a lactonization of β-aryltosylate with an internal ester, a lactone ring transformation, and an ether ring transformation via the Cram’s arenium ion. We also developed a 7-endo selective Friedel-Crafts cyclization of various epoxy unsaturated esters promoted by Lewis acids. Detailed experimental data showed that a spiro [5.5] undecadienyl cation is a key intermediate of this reaction. The reaction mechanism seems to involve ipso-cyclization and subsequent skeletal rearrangement of the resulting spirocyclic arenium ion. The Friedel-Crafts cyclization was also applied to the formation of tetrahydro-2-benzazepine.
Phosphate-modified oligonucleotides in which one of the two non-bridging oxygen atoms of each phosphodiester linkage is replaced by other kinds of atoms or substituents are useful as the basic structures of therapeutic oligonucleotides. These oligonucleotides have stereogenic phosphorus atoms and the development of an efficient method for the stereocontrolled synthesis is one of the unsolved problems. To solve this problem, we developed a novel method using diastereopure nucleoside 3’-O-oxazaphospholidine derivatives as monomers. Proline-derived bicyclic oxazaphospholidine derivatives were found to be the monomers of choice in that they could be synthesized with diastereoselectivity of >99 : 1 and were stable to epimerization. Various phosphate-modified oligonucleotides were synthesized in a stereocontrolled manner by using these monomers. The resultant stereoregulated oligonucleotides enabled us to demonstrate that the hybridizing affinity for complementary RNA was greatly affected by the configuration of the phosphorus atoms.
Four types of ruthenium-catalyzed stereoselective allylic substitutions of monosubstituted allylic esters have been discussed. (1) Highly linear selective allylic alkylation of both branch and linear type allylic acetates with malonate anion by 2-DPPBA ligated Ru3(CO)12 catalyst, and the structure and reactivity of π-allylruthenium intermediate. (2) Highly linear selective allylic amination of both branch and linear type allylic acetates by 2-DPPBA ligated Ru3(CO)12 catalyst. (3) Selecitve substitution at the position originally substituted with leaving group in the allylic alkylation of mono- and disubstituted allylic esters with malonate anion by [RuCl2(p-cymene)]2 with PPh3 or 2-DPPBA catalyst, and the chirality transfer of the optically active allylic esters to the allylic alkylated products. (4) Regio- and enantioselective allylic amination of racemic monosubstituted allylic esters with aliphatic secondary amines by RuCl3 with (S,S)-ip-pybox catalyst.
The benzo-fused seven-membered-ring nitrogen heterocycles (e.g., 1-benzazepine, 1,5-benzodiazepine, and 1,5-benzothiazepine), which have been used as important core structures of various biologically active molecules, possess a exible stereochemical (conformational) nature. When exerting biological activity, the receptors and enzymes should recognize the specic confor-mation of the heterocycles. Conformational change may cause chirality due to the axis. This article describes such axial chirality originating in amide and sulfonamide structures in relation to biological activity. Conformation of the benzo-fused seven-membered-ring was frozen by introducing a methyl group at the peri-position of the benzene ring to enable separation of the (aS)/(aR)-axial isomers originating in the sp2-sp2 axis of the Ar-N(CO) and Ar-N(SO2) moieties. Thus, the conformational and atropisomeric properties of 1N-benzoyl-1,5-benzodiazepine (A), 1,5-benzothiazepin-4-one and its S-oxide (B), N-benzoyl-1,5-benzothiazepine and its S-oxide (C), and 1N-sulfonyl-1,5-benzodiazepine (D) were clarified. In addition, A and C were evaluated as vasopressin receptor ligands to identify the active conformation recognized by the receptor.
Glycosylation reaction is an important class of reactions in organic chemistry, and the development of the method contributes to the synthesis of many biologically active compounds containing various glycoside bonds. Recently, several groups have developed novel glycosylation reactions using gold catalysis, which has unique reactivities, such as high‘alkynophilicity’. In this short review, recent reports about gold-catalyzed glycosylation reactions through the activation of alkyne moieties are described.
Recently, the direct functionalization of unactivated C(sp3)-H bonds have been well developed. Despite their numerous efforts, controlling the site-selectivity in these transformations is still challenging because a multitude of C-H bonds has close dissociation energies. In this mini-review, successful examples to control site-selectivity in C(sp3)-activation reaction by changing reagents or catalysts is described.