Biomedical subjects
Publications and source records attributed to Marcus A Tius.
The PdCl(2)-catalyzed cyclization of alpha-alkoxy dienones leads to 2-hydroxycyclopentenones, whereas the Pd(OAc)(2)-catalyzed reaction leads to cross-conjugated cyclopentenones through an oxidative process. [reaction: see text]
[reaction: see text]. Propargyl vinyl ketones that are derived from the addition of 1-lithio-1-methoxymethoxy-2-ynes to morpholino enamides undergo isomerization followed by cyclization to alpha-methylene cyclopentenones upon exposure to silica gel.
[reaction: see text] A triply convergent synthesis of alpha-methylene cyclopentenones has been demonstrated in which an intermediate C,O-dianion is formed and trapped on carbon by electrophiles.
[reaction: see text] alpha-Lithio cumulenyl ethers can be prepared in situ and converted to alpha-allenyl cyclopentenones. Isomerization of the product of one such reaction has led to a furanyl cyclopentenone, the core structure of nakadomarin A.
The main psychoactive constituent of marijuana, (-)-Delta(9)-tetrahydrocannabinol, produces most of its physiological effects by interacting with the CB1 cannabinoid receptor, a membrane protein belonging to the large superfamily of G-protein coupled receptors. The 3-D structure of the receptor binding site is of value in the design of novel medications for a variety of therapeutic indications. To obtain information on the amino acid residues associated with this binding site, we have designed and synthesized a cannabinergic CB1 ligand prototype carrying an electrophilic isothiocyanato group capable of reacting covalently with amino acid residues bearing thiol or unprotonated amino groups. The ligand also incorporates an iodide atom, which can serve as a high-activity radiolabel. The key step in our synthesis involves a rapid intramolecular Diels-Alder reaction of a transiently formed o-quinone methide, which proceeds stereospecifically with the formation of the tricyclic cannabinoid template. Introduction of the iodo group is the last step in the sequence and is compatible with the use of (125)I-radiolabel.
The variant of the Nazarov cyclization that makes use of allenyl ethers is suitable for the preparation of diverse, highly functionalized cyclopentenones. Three variants of the basic reaction, differing in the nature of the electrophile that is combined with the allene to prepare the precursor for the pentadienyl cation, are described. One variant, which utilizes an alpha,beta-unsaturated morpholino amide, has been successfully employed in an enantioselective version of the cyclopentannelation.
The enantiomeric resolution of a racemic novel cannabinoid receptor ligand conformationally restricted at the southern aliphatic chain was accomplished using a ChiralPak AD column. Both enantiomers were tested for their competitive binding to the rat brain CB1, mouse spleen CB2 and human CB2 receptors. The levorotatory isomer showed exceptionally high affinity for the CB1 receptor with a seven-fold selectivity over CB2.
Commercially available tribromoethylene has been converted to ketoepoxide 15, an advanced intermediate in the total synthesis of guanacastepene A. [reaction: see text]
The scope of an enantioselective cyclopentannelation reaction that makes use of allenyl ether-derived nucleophiles has been probed. The enantioselectivity is induced by a traceless chiral auxiliary that is easily derived from camphor. It has been shown that for gamma-substituted allene ethers that are axially chiral, very high enantiomeric excesses of cyclopentenone products are observed in the matched cases. Two fundamentally different mechanisms are observed, one for the cyclizations of allenyl ketones (see eq 7), the other for the cyclizations of allenyl alcohols (see eq 11). The methodology is versatile, efficient, and well-suited for applications in synthesis.
[reaction: see text] A brief stereospecific synthesis of cryptophycin 1 is described in which (R)-mandelic acid serves as the sole source of asymmetry for unit A. The key step is a hetero-Diels-Alder cycloaddition.