Robert S. Coleman

Diastereoselective addition of vinyl organometallic reagents to l-serinal

Abstract An examination of the diastereoselective addition of vinyl organometalic reagents to N-BOC l -serinal acetonide (1) to afford mixtures of syn-2 and anti-2 is presented. Vinylzinc chloride in nonpolar solvents was found to add to the aldehyde carbonyl of 1 with 6:1 syn/anti stereoselectivity in excellent yields.

A direct and efficient total synthesis of the tubulin-binding agents ceratamine A and B; use of IBX for a remarkable heterocycle dehydrogenation.

The total synthesis of the tubulin-binding agents ceratamine A and B is reported, along with des-methyl analogs, via a synthetic route that is high-yielding and operationally efficient. The synthetic route involved a Beckmann rearrangement to form an azepine ring precursor, a Knoevenagel condensation to install the benzylic side chain, and an effective imidazole annulation onto an alpha-aminoketone precursor with a protected S-methylisothiourea. Final dehydrogenation proved remarkably facile using IBX.

Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics

Anthracycline antibiotics such as daunomycin (Dauno) and doxorubicin (Dox) are well-known clinically used cancer chemotherapeutics, which, among other mechanisms, bind to DNA, thereby triggering a cascade of biological responses leading to cell death. However, anthracyclines are cardiotoxic, and drug resistance develops rapidly, thus limiting their clinical use. We report here the synthesis and DNA-binding affinity of a novel class of functional anthracycline mimetics consisting of an aromatic moiety linked to a carbohydrate (1-12). In the targets, the aromatic core consists of a 2-phenylbenzo[b]furan-3-yl, 2-phenylbenzo[b]thiophen-3-yl, 1-tosyl-2-phenylindol-3-yl, or 2-phenylindol-3-yl group that is bound to one of three aminosugars (daunosamine, acosamine, or 4-amino-2,3,4,6-tetradeoxy-alpha-l-hexopyranoside) via a propargyl linker. The DNA binding affinity of these twelve compounds has been evaluated by using both direct and indirect fluorescence measurements. Compared to Dauno and Dox, the DNA binding affinity of these analogues is weaker. However, both aromatic and aminosugar motifs are critical to DNA binding, with more influence coming from the structural features of the aromatic portion.

Stereocontrolled synthesis of anthracene β-C-ribosides: fluorescent probes for photophysical studies of DNA

Effective, stereocontrolled syntheses of the 1-anthracenyl and 2-anthrancenyl β-C-2′-deoxyribosides are reported and were based on a diastereofacialselective, palladium-catalyzed glycosidation of the corresponding protected (4S,5R)-4-hydroxy-5-(hydroxymethyl)dihydrofuran.

Cycloaddition reactions of acyl ketenes with enol ethers : a general synthesis of 2-alkoxy-2,3-dihydro-4H-pyran-4-ones

Abstract A detailed description of the hetero Diels-Alder reactions of acyl ketenes 4-6 with electron-rich dienophiles 7-9 for the facile synthesis of 2-alkoxy-2,3-dihydro-4H-pyran-4-ones 10-12 is presented.

Synthesis and stability of S-cyanoethyl-protected 4-thiouridine and 2′-deoxy-4-thiouridine

Abstract A convenient preparation of S -(2-cyanoethyl) protected 2′-deoxy-4-thiouridine ( 5a ) and 4-thiouridine ( 5b ) is presented. The S -cyanoethyl protecting group is stable to reagents commonly encountered during the phosphoramidite method of solid-phase oligonucleotide synthesis, and is readily deprotected using concentrated NH 4 OH at 25°C.

Application of a Cu(I)-mediated biaryl cross-coupling reaction to the synthesis of oxygenated 1,1'-binaphthalenes

Abstract Application of an oxidative copper(I)-mediated biaryl cross-coupling protocol to the synthesis of highly oxygenated, differentially substituted 1-1′-binaphthalenes related to the perylenequinone calphostin C is detailed.

Thionucleoside disulfides as covalent constraints of DNA conformation

Abstract Full details of a new strategy for cross-linking of duplex oligonucleotides are described. A direct base-to-base disulfide bond is formed by oxidation of two appropriately positioned thionucleoside bases. Cross-link formation between 4-thio-2′-deoxyuridine and 6-thio-2′-deoxyinosine is demonstrated in three sequence contexts (3′ to 3′, 5′ to 5′, and opposed). Disulfide formation occurs in high yield in both duplex and hairpin DNA. Molecular modeling and circular dichroism were used to demonstrate minimal distortion of the constrained B-DNA double helix.

Total synthesis of strobilurin B using a hetero-bis-metallated pentadiene linchpin

An efficient, six-step stereocontrolled total synthesis of the antifungal agent strobilurin B is reported and was based on a convergent bi-directional coupling featuring a hetero-bis-1,4-metallated pentadiene system as the linchpin.

6-Thio-2′-deoxyinosine: Synthesis, incorporation, and evaluation as a postsynthetically modifiable base in oligonucleotides

Abstract The synthesis of 6-thio-2′-deoxyinosine (d S6 I) in a form suitably protected for solid-phase oligonucleotide synthesis is reported. This thionucleic acid was incorporated in high yield into short oligodeoxynucleotides, and the thiocarbonyl group could be modified by S-alkylation with complete chemoselectivity. The quantitation of incorporation and facile post-synthetic modification was demonstrated by enzymatic digestion and HPLC analysis, and the effect of covalent alkylation was determined by ΔT m measurements of the corresponding duplex oligonucleotides with dC as the complementary base.