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A convenient and practical synthesis of 6-carboalkoxy-13-cycloalkyl-5 H -indolo[2,1- a ][2]benzazepine-10-carboxylic acid derivatives ( 6 ) has been developed. The key step in the synthesis utilizes an intramolecular tandem reaction sequence of a Michael addition followed by a Horner–Wadsworth–Emmons (HWE) olefination reaction between hemi-aminal 11 and methyl 2-(dimethoxyphosphoryl)acrylate 12 . The ring construction occurred efficiently and purification of the products 6 was straightforward. The C-10 methyl ester of 6a was hydrolyzed selectively to the carboxylic acid 13 while the olefin of 6d was converted to the cyclopropane 14 using trimethylsulfoxonium iodide in DMSO in the presence of NaH.

A wide range of amines can be coupled with carboxylic acids via a dimethylaluminum intermediate.

The stable 12-β-hydroxybicyclo[7.1.0] diynene core 15 has been prepared stereospecifically. The key step consists of conjugate addition of dimethylaluminum benzenethiolate to enone aldehyde 12 followed by an in situ titanium isopropoxide assisted aldol cyclization to produce alcohol 13 as a single isomer.

An efficient non cobalt mediated route for the synthesis of a simplified bicyclo[7.3.1]enediyne core of the naturally occurring calicheamicins and espe

A chemoselective approach to functionalize the C-10 position of 10-deacetyl baccatin III, a key intermediate for the semi-synthesis of paclitaxel, is described. The chemistry provides an easy access to a variety of C-10 hydroxyl derivatives, such as, ethers, esters, carbonates, carbamates, and sulfonates under mild conditions. The C-10 modified baccatin derivatives were further employed in the synthesis of novel biologically active Taxol® analogues.

During the screening of the natural products for their ability to inhibit the binding of REV (regulation of virion expression) protein to [33P] labeled RRE (REV responsive element) RNA, two novel fungal metabolites, harziphilone and fleephilone, were isolated from the butanol - methanol (1:1) extract of the fermentation broth of Trichoderma harzianum by bioassay guided fractionation. The structures of these two new compounds were established by spectroscopic methods. Harziphilone and fleephilone showed inhibitory activity against the binding of REV-protein to RRE RNA with IC50 values of 2.0μM and 7.6μM, respectively. However both compounds did not protect CEM-SS cells from acute HIV infection at concentration levels up to 200μg/ml using an XTT dye reduction assay. In addition, harziphilone demonstrated cytotoxicity at 38μM against the murine tumor cell line M-109.

The Stereochemistry of C-6,7 epoxy paclitaxel was determined by single crystal X-ray analysis of the baccatin derivative to be 6α, 7α. Thus finding corrects the structure reported by Kingston et al based on NOE data and corrects the discrepancy reported for facial selectivity of the reaction of osmium tetroxide and dimethyldioxirane with the C-6,7 olefin of paclitaxel.

The synthetic transposition of the 7-hydroxyl group of paclitaxel to the 6-position is described. The route presented prepares both the 6-α- and β-isomers stereospecifically. The key step of this transposition involves the stereoselective reduction of the 6,7-α-thiocarbonate using tributylgermanium hydride.

The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.

Paclitaxel analogues with a sulfur group at the 7β position were required for SAR studies. Attempts to generate these compounds by displacing a 7α leaving group with sulfur nucleophiles were unsuccessful. Instead, these compounds were successfully prepared from a 7β-thiol intermediate that was obtained by a base-catalyzed epimerization of the 7α-thiol derivative. The epimerization presumably proceeds through a thioaldehyde intermediate and exhibits the opposite stereochemical preference of its oxygen counterpart.

New analogues of paclitaxel (1a, active constituent of Taxol®) were synthesized containing an epoxide at the C-10 position. The introduction of the epoxide was carried out by selective removal of the C10-acetate followed by protection of the C2′- and C7-hydroxyl groups. After oxidation to yield a ketone at the C10-position, this intermediate was reacted with dimethylsulfonium ylide. Deprotection and further manipulations provide the C10-spiro epoxide of paclitaxel (1b) and the corresponding C7-MOM ether (1c).

Nitropyridines reacted with an excess of vinyl Grignard reagent to produce 4- or 6-azaindoles. Improved yields were obtained when a halogen atom was present at the position α to the nitrogen atom in the pyridine ring.

An efficient, one-pot Friedel–Crafts acylation/hydrolysis reaction promoted by the acidic ionic liquid 1-ethyl-3-methylimidazolium chloroaluminate (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminum chloride (X(AlCl3), mole fraction X = 0.75) for the formation of 3-glyoxylic acid derivatives of electron-deficient, substituted 4- and 6-azaindoles is described.

The S N Ar-type reaction of the piperidine amide of cyanoacetic acid with a series of heteroaryl halides followed by in situ oxidation of the resultant anion with peracetic acid provided a convenient, one-pot protocol for preparative access to heteroaryl α-keto amides. In this procedure, the amide of cyanoacetic acid functions as an Umpolung-type synthon of the α-keto amide moiety.

Azole-N-acetonitrile derivatives were utilized as synthons for an ambident carbonyl moiety via a strategy relying upon sequential base-mediated S N Ar substitution of a 2-halo heterocycle, in situ oxidation, and amine displacement. This strategy allows prompt and efficient synthesis of N-containing heteroaryl amides directly from the corresponding halides via a one-pot process.

Malononitrile could be utilized as a synthon for the carbonyl moiety via a one-pot process that was initiated via base-mediated S N Ar substitution of a heteroaryl halide. Subsequent peracetic acid oxidation of the resultant anion delivered an electrophilic acyl nitrile in situ that readily reacted with added nucleophiles to afford heteroaryl carboxylic acid derivatives. The reaction of the sodium salt of malononitrile with a series of heteroaryl chlorides followed by the subsequent addition of an amine and peracetic acid provided the corresponding heteroaryl amides.

Dialkylamino acetonitrile derivatives were utilized as alternative to cyanohydrin synthons for preparation of the corresponding heteroaryl dialkyl amides via a strategy of sequential base-mediated coupling and oxidation. The most advantageous oxidant, NiO(2)-H(2)O, can readily oxidize 2-substituted aminoacetonitriles to the corresponding amides under both basic and neutral conditions by forming cyanohydrins in situ.

Conditions for attachment of acetyl chloride, benzoyl chloride, and chloromethyl oxalate to the 3-position of 4-, 5-, 6-, or 7-azaindoles were explored. Best results were achieved with an excess of AlCl(3) in CH(2)Cl(2) followed by the addition of an acyl chloride at room temperature.

The diynene lithium acetylide 5 adds to 2-siloxy-2-cyclohexenone 6 followed by silyl migration to produce ketone adduct 7 , an intermediate towards a simple Esperamicin core