Tomoyuki Yoshimura

Enantiocontrolled Total Syntheses of Breviones A, B, and C

Enantiocontrolled total syntheses of the breviones A, B, and C have been accomplished using a highly diastereoselective oxidative coupling of an α-pyrone with a tricyclic diene prepared from an optically pure Wieland-Miescher ketone derivative through the 7-endo-trig mode of acyl radical cyclization.

Asymmetric α-arylation of amino acid derivatives by clayden rearrangement of ester enolates via memory of chirality

A method for asymmetric α-arylation of amino acid derivatives has been developed. The arylation was performed by Clayden rearrangement of ester enolates via memory of chirality to give hydantoins with an aryl-substituted tetrasubstituted carbon with up to 99% ee.

Axially Chiral Binaphthyl Surrogates with an Inner N-H-N Hydrogen Bond

Novel chiral binaphtyl surrogates with an inner hydrogen bond have been created. The NH appears at 13.0-13.3 ppm in thier (1)H NMR spectrum, indicating extremely strong hydrogen bonding. Enantiomers of these compounds were stable at ambient temperature and separable by HPLC with a chiral stationary phase. The half-lives of racemization of the enantiomer are in the range 3 months to 2 years at 20 degrees C, and the barriers for racemization are in the range 27.0 to 28.2 kcal/mol. An X-ray crystal analysis of the compound (R = CHPh(2)) shows that the pseudonaphthyl skeleton including CN...HN is almost completely planar and the dihedral angle between the pseudonaphthalene and naphthalene rings is 128 degrees .

Asymmetric Intermolecular Conjugate Addition of Amino Acid Derivatives via Memory of Chirality: Total Synthesis of Manzacidin A

Asymmetric intermolecular conjugate addition of α-amino acid derivatives with 4 via memory of chirality has been developed. The reactions proceeded in up to 98% ee with retention of configuration at the newly formed tetrasubstituted carbon center when R = Me. The product (R = Me) was transformed into manzacidin A.

Asymmetric aldol reaction via memory of chirality

Asymmetric aldol reactions of α-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation.

Asymmetric Induction via Short-Lived Chiral Enolates with a Chiral C–O Axis

A novel method has been developed for the asymmetric cyclization of alkyl aryl ethers. The reactions were assumed to proceed via short-lived chiral enolate intermediates with a chiral C-O axis to give cyclic ethers with tetrasubstituted carbon in up to 99% ee. The half-life of racemization of the chiral enolate intermediate was roughly estimated to be ~1 s at -78 °C.

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β-Lactams with contiguous tetra- and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4-exo-trig cyclization of axially chiral enolates generated from readily available α-amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β-lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β-lactam enolates thus formed through reversible intramolecular conjugate addition (4-exo-trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work-up procedure) to give β-lactams in up to 97% ee.

Insights into the origins of configurational stability of axially chiral biaryl amines with an intramolecular N-H-N hydrogen bond.

Configurationally stable chiral biaryl amines with an intramolecular N-H-N hydrogen bond have been developed. The barriers for racemization are in the range of 19.3-28.2 kcal/mol, which corresponds to the half-lives of racemization of the enantiomers in the range of 7 s to 2 years at 20 degrees C. Enantiomers of some of these compounds were separable by HPLC with chiral stationary phases. The biaryl amines are supposed to have a conformation similar to that of a binaphthyl skeleton, which was indicated by an X-ray crystal analysis of a biaryl amine. The N-H appears at 11.1-13.3 ppm in their (1)H NMR spectrum in CDCl(3), indicating strong hydrogen bonding. Biaryl amines with an extremely strong intramolecular N-H-N hydrogen bond (delta(NH) approximately 13 ppm) were assumed to undergo racemization without cleavage of an N-H-N hydrogen bond, while those with a mediumly strong N-H-N hydrogen bond (delta(NH) approximately 11 ppm) are assumed to undergo racemization via cleavage of an N-H-N hydrogen bond. Hydrogen/deuterium exchange of a chiral biaryl amine was found to proceed without any trace of racemization.

Dipicolylamine as a unique structural switching element for helical peptides

Developing novel methods for metal-induced switching of peptide structures expands the design principles of functional biomolecules and biomaterials. Here, a simple method for on-resin synthesis of dipicolylamine (Dpa)-containing peptides was developed. Whereas addition of divalent metal ions such as Fe(ii) and Cu(ii) to a peptide bearing a pair of Dpa moieties at the i and i + 4 positions led to the formation of a 1:1 complex of Dpa with metals, addition of Ni(ii) yielded a cross-linked structure of Dpa-metal (2:1). This feature was utilized for the selective detection of Ni(ii) using the peptide-Fe(ii) complex. Repeated switching of the helical structure was also achieved by multiple additions of divalent metal ions to the peptide.

α-Arylation of α-Amino Acid Derivatives with Arynes via Memory of Chirality: Asymmetric Synthesis of Benzocyclobutenones with Tetrasubstituted Carbon

A method for asymmetric α-arylation of α-amino acid derivatives via memory of chirality has been developed. Addition of axially chiral enolates, generated from α-amino acid derivatives, to in situ generated arynes, followed by intramolecular C-acylation of the resulting aryl metallic species, gave benzocyclobutenones with a tetrasubstituted carbon with retention of configuration in up to 99% ee.