A synthesis of (±)-thia-calanolide A, its resolution and in vitro biological evaluation.

A synthesis of (±)-thia-calanolide A 3 has been successfully accomplished starting from 3,5-dimethoxythiophenol 4, in six steps in an overall yield of 4.5%. The key reaction involved Friedel-Crafts tigloylation of 5,7-dihydroxy-4-n-propyl thiocoumarin 6 employing an appropriate solvent of CS2-PhNO2 in a ratio of 7:3. In its biological evaluation for anti-HIV activity, (±)-thia-calanolide A 3 demonstrated comparatively less activity with calanolide A and its synthetic analogue aza-calanolide. Further, (±)-3 has been resolved by chiral HPLC to (+) and (-)-3.

Total synthesis and determination of relative and absolute configuration of multiplolide A.

A flexible approach for total syntheses of possible multiplolide A diastereomers establishing the relative and absolute configuration is documented. The adopted strategy features ring-closing metathesis (RCM) as the key reaction and screening of a set of substrates for the feasibility of RCM in general and for the requisite E-configuration of ring olefin in particular. Selective protecting groups manipulation prior to the assembly of the central macrocyclic core was instrumental in installing the epoxide functionality on a fully deprotected nonenolide at the end of the synthesis.

Practical syntheses of 4-fluoroprolines.

4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.

The future lies in chiral purity: a perspective.

Racemates are fixed-dose combinations of stereoisomers. Each isomer may have different pharmacokinetic or pharmacodynamic properties. Recent research has allowed appreciation of the need to purify racemates and develop useful unichiral molecules. Some examples are: S-amlodipine besylate, S-atenolol, S-metoprolol succinate, S-pantoprazole sodium and R-ondansetron hydrochloride.

Total syntheses of schulzeines B and C.

Schulzeines B (2) and C (3) were synthesized by a convergent strategy using epimeric tricyclic lactam building blocks, 4 and 5, and the C28 fatty acid side chain 6. Syntheses of tricyclic lactams (4/5) were achieved by Bischler-Napieralski reaction. Sharpless asymmetric dihydroxylation and BINAL-H-mediated asymmetric reduction of an enone was employed to prepare the key fatty acid side chain 6. The spectral as well as analytical data of 2 and 3 were in good agreement with the reported data for the natural products, thus confirming their assigned structures.

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents.

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.

A carbohydrate-based approach for the total synthesis of 1,3-polyol/alpha-pyrone antifungal natural products.

[Chemical reaction: see text] An elimination and stereoselective hydrogenation of alpha-D-glucoheptonic-gamma-lactone derivative has been applied to prepare a differentially protected anti,anti-1,3,5-triol system, the utility of which has been extended for the total synthesis of anti-fungal 1,3-polyol/alpha-pyrone natural products.

Synthesis of eupomatilone-6 and assignment of its absolute configuration.

[Reaction: see text]. The Zn-mediated Barbier reaction of the biarylaldehyde 8 with crotyl bromide followed by hydroboration and oxidation provided the gamma-butyrolactones 4 and 5. The stereoselective installation of methyl group at C-3 by using LiHMDS and MeI completed the synthesis of racemic eupomatilone-6 (2) and its diastereomer 3. The spectroscopic data of 2 was in full agreement with reported spectra of natural product, thus confirming the revised relative configuration of eupomatilone-6. Similarly, an optically active (3R,4R,5S)-isomer of eupomatilone-6 (23) was prepared in which the aldol reaction with thiazolidinethione as a chiral auxiliary was employed as a key step. On the basis of the spectroscopic data and optical rotation values of 23, the absolute configuration of eupomatilone-6 was proposed.

Synthesis of the putative structure of eupomatilone-6.

[reaction: see text] The synthesis of eupomatilone-6 (1) has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular Horner-Wadsworth-Emmons reactions. The spectroscopic studies carried out on synthetic eupomatilone-6 do not agree with those reported for the natural product, and therefore revision of the assigned structure is warranted.

Synthesis of spirocycles via ring closing metathesis of heterocycles carrying gem-diallyl substituents obtained via ring opening of (halomethyl)cyclopropanes with allyltributyltin.

In the presence of allyl tri-n-butyltin--AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.

Carbohydrate-based synthesis of naturally occurring marine metabolites slagenins B and C.

[reaction: see text] The first enantioselective syntheses of slagenins B and C, marine metabolites from Agelas nakamurai, starting from L-arabinose have been described.

Conformational studies by dynamic NMR. 91. Conformational stereodynamics of tetraethylmethane and analogous C(CH2X)4 compounds.

Variable-temperature NMR studies of tetraethylmethane (1a), tetrapropylmethane (1b), tetrachloromethylmethane (1c), tetrabromomethylmethane (1d), tetracyclopropylmethylmethane (1e), and tetrabenzylmethane (1f) show a range of dynamic behavior. Separate signals for two types of conformation are observed for 1a, 1c, and 1d at low temperatures, with more than 95% of the molecules in a time-averaged D2d conformation, and the S4 conformation as the minor populated alternative. Compound 1e populates only S4-type conformations but equilibrates slowly between degenerate versions of these at low temperatures. Compounds 1b and 1f show a temperature-dependent spectrum but the low-temperature limit spectrum could not be observed. Ab initio calculations agree well with experiment on the conformational equilibria and suggest in particular that compounds 1b and 1f behave similarly to compounds 1a and 1e, respectively. A crystal structure of compound 1f is reported.

An expedient synthesis of tetrakis(cyclopropylmethyl)methane.

Synthesis of tetrakis(cyclopropylmethyl)methane, a new symmetric product has been described using the radical mediated gem-diallylation of cyclopropylmethyl xanthate as a key step and its single crystal X-ray analysis established its C2-symmetry.