A novel, recyclable, thiourea-based asymmetric organocatalyst containing a hydrophobic anchor has been developed. The chemical nature of the hydrophobic anchor contributes to the desirable characteristics of the recyclable catalyst. The hydrophobic anchor-tagged thiourea catalyst is highly soluble in less polar solvents, which is compatible with amino thiourea catalyst-mediated asymmetric reaction conditions, but sparingly soluble in polar solvents used for the recycle process. This asymmetric catalyst delivers a catalytic performance comparable to that of a parent catalyst and can be readily recycled from reactions.Access to a wide variety of chiral compounds requires that asymmetric catalysts perform well in the construction of chiral centers. Amongst known efficient asymmetric catalysts, organocatalysts have attracted attention increasingly because they are cost-effective, less toxic, and operationally simple compared with conventional metal catalysts. [1] Amino thiourea catalysts are dual-activating organocatalysts which simultaneously activate both an electrophile and a nucleophile in a highly enantioselective reaction, affording a chiral product. [2] For example, Takemoto's thiourea catalyst 1 has been applied to a variety of asymmetric reactions ( Figure 1). [2c] In comparison with the asymmetric metal catalysts, a weak point of organocatalysts is that relatively large amounts of the catalyst load must be used. Because of this, recyclable organocatalysts have been designed to extend the synthetic utility of organocatalysts. [3] Recyclable thiourea catalysts that have been developed to date have an insoluble resin support, [4a,b] a polyethylene glycol (PEG) moiety, [4a] or a fluorocarbon carrier [4c,d] as shown in Figure 1. A poly styrene-type insoluble resin support in a catalyst 2 allows for easy recovery of the catalyst from a reaction, typically by filtration, but the two-phase reaction using a resin-supported catalyst generally results in reduced catalytic activity. PEG as a carrier can be used in solution and leads to a more favorable reaction outcome. A drawback of PEG catalysts such as 3 is that difficulties in the control of the solubility can lead to low efficiency in the recovery. Recently, catalysts 4 and 5 with a perfluoroalkyl chain were independently developed by Cai [4c] and Miura. [4d] Such fluorine-containing catalysts have a high affinity for fluorinecontaining solvents or silica gel. These features allow the fluoroalkyl catalyst to be separated by extractive or chromatographic work-up using fluorine-containing solvent. Such solvents may however be expensive.In this context, we envisioned that the use of a hydrophobic anchor tag consisting of an extended alkyl chain as a carrier could be used in the development of a novel recyclable catalyst which can overcome the drawbacks mentioned above. Hydrophobic anchors have been independently developed by Tamiaki and Chiba and Takahashi for use in peptide synthesis. [5] Generally, such anchors enhance the solubility of the tagged molecu...

The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides containing a 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA unit could be isolated under ultra-mild deprotection conditions (50 mM K2CO3 in MeOH at room temperature for 4 h). Moreover, by treatment with various amines as a post-synthetic modification, the oligonucleotides were successfully converted into the corresponding 2′-N-alkylaminocarbonyl-2′-amino-LNA (2′-urea-LNA) derivatives. The duplex- and triplex-forming abilities of the synthesized oligonucleotides were evaluated by UV-melting experiments, which showed that 2′-urea-LNAs could stabilize the nucleic acid complexes, similar to the proto-type, 2′-amino-LNA. Thus, 2′-urea-LNAs could be promising units for the modification of oligonucleotides; the design of a substituent on urea may aid the formation of useful oligonucleotides. In addition, pentafluorophenoxycarbonyl, an amino moiety, acted as a precursor of the substituted urea, which may be applicable to the synthesis of oligonucleotide conjugates.

We describe herein a manganese(IV) oxide-mediated oxidation of N-p-methoxyphenyl (PMP)-protected glycine derivatives for the synthesis of α-imino carboxylic acid derivatives. Using this methodology, utilization of unstable glyoxic acid derivatives was avoided. Furthermore, using this methodology we synthesized novel α-imino carboxylic acid derivatives such as α-imino phenyl ester, perfluoroalkyl etsers, imides, and thioester. The asymmetric Mannich reaction of those novel imine derivatives with 1,3-dicarbonyl compound is also described, and the novel α-imino imide gave improved chemical yield and stereoselectivity compared with those obtained by the use of the conventional α-imino ester-type substrate.Key words α-imino carboxylic acid derivative; heterogeneous oxidant; asymmetric organocatalysis; thiourea; unnatural α-amino acid Unnatural α-amino acids are often seen in varieties of biologically active compounds, 1-4) including pharmaceutics, and have been used as indispensable chiral building blocks for the synthesis of such active compounds.5,6) Additionally, increasing utilities of unnatural amino acids as a key structural element have also been shown in fields of chemical biology and asymmetric transformation.7-11) These contexts evoke much interest of synthetic chemists in asymmetric synthesis of the structural unit.12,13) Enabling easy access to diverse α-amino acids only by changing nucleophiles employed, Mannich-type reaction of α-imino ester has been widely utilized for the asymmetric synthesis.14-20) Generally, condensation of glyoxalates and primary amines affords α-imino esters as the requisite substrate for Mannich-type reaction (Chart 1a); however, the glyoxalates are unstable, and suffer easy hydrolysis or polymerization at room temperature. Additionally, high susceptibility of the resulting α-imino ester to silica gel has forced us to directly use the imino esters for the Mannich reaction without purification, thereby leading to difficulty in maintaining the reaction outcome. In this context, cross-dehydrogenative coupling (CDC) has been investigated for the synthesis of α-functionalized amino acids 21-23) (Chart 1b). The CDC protocol features oxidative preparation of α-imino ester from glycinates with the use of the oxidants such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), CuOAc, Ru(bpy) 3 Cl 2 / light (or N-oxyl radical), or Cu(I)/molecular oxygen, followed by in situ Mannich reaction. Although the CDC protocol is free from the use of unstable glyoxalates, the in situ Mannich reaction has to be performed in the presence of the employed oxidant due to difficulty in achieving complete separation of the imino ester and oxidant, by which the use of the CDC remains within application to the coupling of oxidant-tolerant functional units. Here, we envisioned that the heterogeneous oxidation system enabling facile removal of insoluble oxidants by filtration allowed the imino ester to be readily obtained and subsequently subjected to Mannich reaction under oxidant-free conditions (Chart 1c).

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