A Convenient Method for Preparation of α-Imino Carboxylic Acid Derivatives and Application to the Asymmetric Synthesis of Unnatural α-Amino Acid Derivative

Abstract

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).

Asymmetric Synthesis of α‐Amino Phosphonic Acids using Stable Imino Phosphonate as a Universal Precursor

“…[11] The trityl groups of 7a-c were then exchanged with an Nps group by removing the trityl group under acidic conditions followed by treatment with NpsCl. Thus-obtained 8a-c were oxidized with MnO 2 [12] to give the desired imino phosphonates 5a-c.A se xpected, 5a-c, as well as the corresponding imino amide, were sufficiently stable to be purified by silica gelc olumn chromatography. [9,13] After successfully preparing substrates 5a-c,w ee xamined the conditions for asymmetric addition.…”

Remote Electronic Tuning of Chiral N‐Heterocyclic Carbenes

“…[11] However, such substitutions affect not only the electronic character of the NHCs but also the steric and electrostatic natures around the reactive carbene sites; therefore, it would cause undesirable effect on catalytic activities. During our efforts to develop the novel asymmetric catalytic reactions, [12] we found that an electronwithdrawing substituent at the indane benzene ring, which is far from the carbene carbon atom, significantly improved the performance of NHC (Figure 1). [13] We were pleased but surprised by this finding because the long distance between the carbene carbon and the substituted site seemed to be beyond the range of the inductive effect.…”

Novel methodology for the synthesis of a-indolyl-glycine containing peptide via direct asymmetric Friedel–Crafts reaction to peptidyl imine

“…Next, MnO2-mediated oxidation of 2 was performed under our previously established conditions to give α-imino peptide 3. [5] In the presence of BINOL-derived chiral phosphoric acid 4 [6], an asymmetric Friedel-Crafts reaction of 3 and indole successfully produced α-indolyl glycine-containing adduct 5. Indole of this adduct 5 was then protected by an Alloc group by Alloc-imidazole [7].…”