Molecular Conversion Laboratory

http://www.sci.osaka-cu.ac.jp/chem/henkan/index_e.html

Current Research and Principal Research Interests
Selected Publications
1. Current Research and Principal Research Interests(1) Synthetic Methods and Total Synthesis of Bioactive Natural Products (1980~present)More than seven hundred amino acids, so-called unusual, unnatural or non-proteinous aminoacids, have been found from the nature as a free form or a constituent of peptide. Theseamino acids have attracted much scientific attention due to their important biologicalactivities such as antibiotics, metal chelators, neurotoxins, and enzyme inhibitors. We haveworked continuously on the syntheses of these natural products based on the developmentof new methods required to overcome the key step for their total synthesis. Representative
examples are the total synthesis of mugineic acid (metal chelator from wheat root), domoic
acid (neuroexcitatory amino acid from red algae), echinocandin D (anti-fungi and anti-yeast
activity from), and galantin I (anti-bacterial activity from). Among these studies, methods for the reductive amination to connect aminoacid linkage, stereoselective construction of 1,2- and 1,3-amino hydroxy systems,
interconversion of amino protective groups via a silyl carbamate, and related methods havebeen reported (1980-1993). Our recent synthetic efforts have focused on the synthesis ofnatural products and related artificial amino acids (β-substituted analogs of β-amino acid)possessing an amino group attached to a quaternary carbon center. These compounds havebeen viewed as having increasing importance not only because of their significant biologicalactivities but also their restricted conformations. We have developed an efficient method forthe synthesis of optically active β-substituted amino acids using an asymmetric version ofStrecker synthesis. Thus, various types of β-substituted β-amino acids have beensynthesized in optically active form, e.g., a potent Leu-enkephalin analog incorporating oneof the synthetic β-substituted amino acids, (1R,2S)-1-amino2-hydroxycyclohexanecarboxylic acid [(1R,2S)-Ahh], the Corey intermediate of lactacystein(neurotropic factor from Streptomyces sp) (1994-1999), a bromopyrrole alkaloid manzacidin
A and C (enzyme inhibitor from marine sponge, 2000), kaitocephalin and its 7- and/or
9-epimers (glutamate antagonist, 2004), and 5,6,11-trideoxytetrodotoxin (2005). We are
currently working on the total synthesis of tetrodotoxin (ion channel blocker) andamathaspiramide F (antibiotic).

(2) Development of Conformationally Restricted Glutamate Analogs to Investigate MolecularFunctions of Neuroexcitaory Amino Acid (EAA) Receptors (1987~present)
Glutamate receptors at many synapses in mammalian central nervous systems (CNS) are
implicated in the construction of memory and early learning as well as in the pathogenesis ofneuron damage to cause various neuronal diseases. We have studied the conformational roleof glutamate when it binds to the receptors through the synthesis of conformationallyrestricted analogs of glutamate, i.e., L-2-(carboxycyclopropyl)glycines (CCGs) and their
3'-substituted analogs (MCGs and DCG-IV). This work has demonstrated that not only did
the receptors and transporters require a specific conformation of glutamate, but also theanalogs can be used as tools for the neuropharmacological research as well as leadcompound for neuroptotecting medicine (1987-2000). We, recently, have performed (1) thesyntheses of new EAA ligands whose conformations are strictly or partially restricted by acarbocycle or an β-substitition of glutamate using the method described in (a), (2)pharmacological characterization of the synthetic glutamate analogs to glutamate receptors;and (3) exploration of neuroactive amino acids and amines from wasp venom. Thus, several
new and sub-type selective agonists for the glutamate receptors have been synthesized(LY354740 and β-hydroxymethyl- and alkoxymethyl-L-glutamate) and a β-carbon analogsof threo-β-hydroxy aspartate and β-benzyl aspartate by the use of a [3.3] sigmatropic
rearrangement of β-acyloxysilane.

(3) Chemical Studies on 3,4-Diohydroxy-3-cyclobutenedione (Squaric Acid) as a Multiple
Functional Group. Development of Squaryl Group-Containing Bioactive Molecules (1995present)
The 4-hydroxy-2,3-dioxocyclobut-1-enyl group (squaryl (Sq) group) is characterized by its
strong acidity (pKa = 1), aromaticity, and chelating ability with metals. We envisioned that SQ
group can be utilized as an isostere of carboxylic acid and as a marker molecule foranalyzing peptide sequences. Initial approach was its incorporation into the γ-position ofglutamate connected with a carbon-carbon bond to obtain molecular stability against
hydrolysis (1995-2000). Recent progress is summarized as follows: (1) incorporation of
SQ-containing glutamate and aspartate into spider and wasp polyamines. SQ-Aspcontaining NPTX-8 exhibited paralytic activity to cricket which was much potent thannatural NPTX-8, (2) synthesis of β-amino squaric acid as an isostere of various β-aminoacid using an addition of dianion enolate derived from β-amino acid ester todiisopropylsquarate as the key step, and (3) chemoselective introduction of the squarylgroup into the N-terminal of biologically active peptide for simplifying the amino acidsequencing by MS/MS analysis) (2001-2005).

2. Selected Publications
1. "Total Synthesis of (-)-Kaitocephalin", M. Kawasaki, T. Shinada, M. Hamada, and Y. Ohfune,
Org. Lett., 7, 4165-4167 (2005).
2."Asymmetric Strecker Route toward the Synthesis of Biologically Active -α, α-Disubstituted
β-Amino Acids", Y. Ohfune and T. Shinada., Bull. Chem. Soc. Jpn., 76, 1115-1129 (2003).
3."Total Synthesis and Absolute Structure of Manzacidin A and C", K. Namba, T. Shinada, H.
Teramoto and Y. Ohfune, J. Am. Chem. Soc. , 122, 10708-10709 (2000).
4. "Efficient Synthesis of a Novel 4-Hydroxy-2,3-dioxocyclobut-1-enyl Group Containing
Amino Acids", T. Shinada, K. Hayashi, T. Hayashi, Y. Yoshida, M. Horikawa, K. Shimamoto, Y.
Shigeri, N. Yumoto, and Y. Ohfune, Organic Lett., 1, 1663-1666 (1999).
5. "Synthesis and Conformational Analysis of Glutamate Analogs. 2-(2-Carboxy-3- substitutedcyclopropyl)glycines as Useful Probes for Excitatory Amino Acid Receptors", K. Shimamoto
and Y. Ohfune, J.Med. Chem. , 39 , 407-423 (1996).
6. "Efficient Syntheses of the Four Enantiomers and Diastereomers of α-Methylthreonine andBoth Enantiomers of α-Methylserine", S.-H Moon and Y. Ohfune, J. Am. Chem. Soc., 116,7405-7406 (1994).
7. "Synthesis of L-2-(2,3-Dicarboxycyclopropyl)glycines. Novel Conformationally Restricted
Glutamate Analogues", Y. Ohfune, K. Shimamoto, M.Ishida, and H. Shinozaki, Bioorg. Med.
Chem. Lett., 3, 15-18 (1993).
8. (a) "Syntheses and Reactions of Silyl Carbamates. 1. Chemoselective Transformations ofAmino Protecting Groups", M. Sakaitani and Y. Ohfune , J. Org. Chem., 55, 870- 876 (1990).
(b) "Syntheses and Reactions of Silyl Carbamates. 2. A New Mode of Cyclic Carbamate
Formation from tert-butyldimethylsilyl Carbamate", M. Sakaitani and Y. Ohfune , J. Am. Chem.
Soc., 112, 1150-1158 (1990).
9. (a) "Total Synthesis of Echinocandins. 1. Stereocontrolled Syntheses of the Constituent
Amino Acids", N. Kurokawa and Y. Ohfune, J. Am. Chem. Soc., 108, 6041-6043 (1986). (b)"Total Synthesis of Echinocandins. 2. Total Synthesis of Echinocandin D via Efficient Peptide
Coupling Reactions", N. Kurokawa and Y. Ohfune, J. Am. Chem. Soc. , 108, 6043-6045 (1986).
10. "Total Synthesis of (-)-Domoic Acid. A Revision of the Original Structure", Y. Ohfune andM. Tomita, J. Am. Chem. .Soc., 104, 3511-3513 (1992).