This account describes our first total synthesis of an enantiomeric pair of FR900482 (1 and ent-1), which was accomplished in a convergent manner utilizing the aromatic segment 14 and the aliphatic segment 15 and ent-15 accessible from commercially available 5-hydroxyisophthalic acid (16) and each enantiomer of diethyl tartrate (17 and ent-17), respectively. The method for the total synthesis involves the following four key steps : (i) coupling reaction of 14 with 15 (14+15→32, Scheme 5); (ii) intramolecular aldol reaction of the highly functionalized dialdehyde 13 (13→36, Scheme 6); (iii) epimerization at the C-8 position of the hydroxy ketone 40 (40→41, Scheme 7); (iv) internal hemiacetal formation of the N-hydroxylamino ketone 11 in situ generated from the ketone 45 (45→11→10, Scheme 10). The in vitro cytotoxicity assay of the synthesized compounds (1, ent-1, 50, ent-50, 51, and ent-51) against P388 murine leukemia cells disclosed that 1 and its congeners 50, 51 possessing natural absolute configuration are ca. 100 times more cytotoxic than the corresponding unnatural enantiomers (ent-1, ent-50, ent-51).
In this account we would like to present our recent developments in copper catalyzed or mediated carbon-carbon bond formation reactions of zirconacycles as well as reactions of related alkenylzirconocene compounds.
The first total synthesis and development of a variety of natural products have been accomplished by using carbohydrates as chiral sources. The target molecules are glycosidase inhibitors (cyclophellitols and nagstatins), central nervous system-affecting products (deacetyl-caloporosides and calbistrin A) and nonsteroidal progesterone receptor ligands (PF1092 substances).
A series of optically active α, α-disubstituted α-amino acids have been synthesized starting with an achiral or a racemic 2-hydroxy ketone. The key transformation to the present synthesis is an intramolecular version of Strecker synthesis. An α-keto ester having a chiral amino acid as the ester group afforded cyclic amino nitrile, in a highly stereoselective manner, in which the amino group and the chirality were diastereoselectively transplanted into the internal ketone group via an imine-enamine equilibrium of the cyclic ketimine intermediate. Oxidation of the amino group followed by removal of the resulting imino group and hydrolysis of the nitrile group afforded α-hydroxymethyl α-amino acid. The use of L-amino acid as the chirality transferring group gave R enantiomer, and its S enantiomer was obtained when D-amino acid was employed. The syntheses of optically active α-substituted serines, α-methylthreonines, and 1-amino-2-hydroxycycloalkanecarboxylic acids are described.
Diphenyl(1-methylpyrrolidin-2-yl)methanol (DPMPM) and N, N-dibutylnorephedrine (DBNE) are highly enantio- and chemoselective chiral catalysts for the addition of dialkylzincs to various aldehydes, affording sec-alcohols with high enantiomeric excesses. Heterogeneous chiral catalyst supported on polystyrene is also highly enantioselective. Pyrimidyl and quinolyl alkanols are asymmetric autocatalysts with amplification of enantiomeric excess in the enantioselective isopropylation of aldehydes. Enantioselective addition of dialkylzincs to N-diphenylphosphinylimines and conjugate addition to enones are performed using N, N-dialkylnorephedrines.
Various types of bis-chalcogenides and their monooxides which have the two chalcogen atoms in close proximity can be activated photochemically or chemically to generate a reactive species such as o-quinodimethane or to promote dealkylation reactions. These molecular activations proceed via intramolecular through-space interaction between the two chalcogen atoms or the formation of σ-bonded dichalcogenadication. Intermolecular through-space and intramolecular through-bond interactions as new modes are also described.
Synthetic potential of the simple heterocycle, 2-oxazolone, as a building block for 2-amino alcohols has been reviewed. Stereodefined introduction of easily replaceable groups to the olefinic moiety of the 2-oxazolone ring, followed by stereospecific and stepwise substitution, works well as a versatile strategy for the chiral synthesis of a wide variety of 2-amino alcohols of biological interest. Sterically constrained chiral 2-oxazolidinones and the derived 2-amino alcohols which are derived from cycloaddition of the 2-oxazolone to cyclic dienes such as anthracenes and cyclopentadiene have general use as excellent auxiliaries and ligands in asymmetric synthesis.
The biomimetic oxidation of dihalogenated phenols employing TTN or electrolysis, effected the construction of a diaryl ether linkage, leading to the syntheses of isodityrosine natural products. In particular, the halogen substituents were found to control the oxidation-direction. The vancomycin derivatives were also synthesized, and their interaction to models of bacterial cell wall precursors were observed by NMR techniques, coupled with the theoretical calculations.
Stereoselective intramolecular bis-silylation reactions catalyzed by isonitrile-palladium (O) complexes are described. Their useful synthetic applications were demonstrated by stereoselective asymmetric synthesis of a natural product and building blocks, e.g., (-) -avenaciolide was synthesized from (R) -3-vinyl-1-undecen-4-ol, and highly enantio-enriched allylsilanes and allenylsilanes were synthesized from the corresponding optically active allylic and propargylic alcohols, respectively. Attempts at catalytic intramolecular asymmetric bis-silylation with optically active t-alkyl isocyanide complexes are also described.
Macrocyclic polyamines are a new class of multifunctional molecules (e. g., complexing agents for cations, anions and neutral molecules). Recently, a new insight into zinc enzyme chemistry has been achieved by studies of multinuclear zinc (II) complexes with macrocyclic polyamines. These complexes serve as both the structural and functional models for the active centers of multinuclear zinc (II) -containing phosphatases (e. g., alkaline phosphatase, and protein serine/threonine phosphatase-1) and have given answers to some basic questions that surround the intrinsic properties of metal ions in those enzymes.