The synthesis of new chloramphenicol-base-derived thiourea organocatalysts, (1S,2R)-12 a–f and (1R,2R)-15 a–c, and their use in the enantioselective alcoholysis of meso-anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)-12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)-15 a–c. This technique was used to synthesize (R)-(−)-baclofen.

Here we report the asymmetric amination of 3-(2-oxoindolin-3-ylidene)butanoates catalyzed by a cinchona-derived alkaloid, yielding products with an N-containing stereocenter in high yields and moderate enantioselectivity. The developed process could be an attractive approach for the synthesis of chiral amino acids.

The highly efficient asymmetric vinylogous Michael addition of 3-(2-oxoindolin-3-ylidene)butanoates to nitroalkenes, catalyzed by a cinchona-based squaramide, is described. The enantioselectivity (up to 99 % ee) and diastereoselectivity (>20:1 d.r.) of the reaction is excellent.

Asymmetric thiolysis of prochiral cyclic anhydrides was achieved with our developed chiral sulfonamide and squaramide bifunctional organocatalysts based on amino alcohol scaffolds. The corresponding thioesters were obtained in high yields with excellent enantioselectivities. The usefulness of this methodology was demonstrated in the enantioselective synthesis of pregabalin.

An enantioselective asymmetric total synthesis of (+)−biotin (1) via the Hoffmann–Roche lactone–thiolactone strategy has been accomplished from commercially available cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid (2). Strategic transformations include a cinchona alkaloid-based bifunctional thiourea mediated methanolytic desymmetrization of prochiral cyclic anhydride 3 to produce the enantiomerically enriched precursor of Roche lactone 5 and an improved introduction of the 4-carboxybutyl side chain at C-4 position of Roche thiolactone 6 via Grignard reaction.

Lung cancer causes serious health problems. Clinical diagnosis of lung cancer relies on histopathological evalution of tissue specimen. However, extensive knowledge of the metabolic biochemistry of tumors can potentially provide important information for accurate diagnosis of lung cancer. High resolution magic-angle spinning NMR spectroscopy has emerged and be widely acknowledged as an excellent tool in investigating tissue metabolism. Moreover, the combination of high resolution magic-angle spinning NMR technique and multivariate data analysis has become an important metabonomics platform for studying the intact biological tissues. This study reported the metabonomic characteristics of 51 lung tissues from 17 patients with lung cancer using the high resolution magic-angle spinning 1H NMR spectroscopy and the multivariate data analysis methods including principal component analysis and orthogonal partial least squares-discriminant analysis. Clear differences among the metabonomic characteristics of lung cancer tissues at various sites were disclosed. Compared with the adjacent noninvolved tissues, the lung cancer tissues had significantly high levels of aspartate, phosphocholine, glycerophosphocholine and lactate but significantly low levels of glucose and valine. Furthermore, significantly positive (or negative) correlations were observed between the levels of some metabolites such as lactate, fatty acids, valine, phosphocholine, and glycerophosphocholine. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.

A highly enantioselective sulfa-Michael addition (SMA) of various thiols to α,β-unsaturated N-acylated oxazolidinones has been achieved with a chiral squaramide catalyst under very mild reaction conditions. In addition, the conversion of the β-thio-substituted adduct to the corresponding methyl β-tosylbutanoate was demonstrated in high yield through a methanolysis/oxidation sequence.

Colorectal cancer (CRC) is the third commonest malignancy cancer worldwide. Clear understandings of global metabolic profiling of the normal mucosa and cancer tissues are vitally important to aid optimizing the clinical management strategy and understanding CRC biology. We studied metabolic characteristics of 20 CRC and 20 distant normal mucosa tissues extracts from 20 patients using high resolution ¹H NMR spectroscopy in conjunction with multivariate analyses, such as principal component analysis (PCA). Compared with distant normal mucosa tissues, lactate, taurine, ornithine and polyamine were present at significantly higher levels in CRC tissue extracts whereas myo-inositol was present at significantly lower level. Two metabolites ratios such as myo-inositol/taurine and myo-inositol/(ornithine+polyamine) appear to be the most valuable biomarkers for the differentiation CRC from normal mucosa tissues. Our data suggested that HR ¹H NMR spectroscopy combined with multivariate analyses is a potentially useful technology for detecting malignant changes in the normal mucosa tissues, the technique may be further exploited for future CRC biomarker research or identification of targets for therapeutic manipulations.

A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C-4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)-1 in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC₅₀ values in the range of 1.7–13.2 nM. Of these compounds, 2-bromophenyl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazone (9 k) displayed the most potent anti-HIV-1 activity (EC₅₀=1.7±0.6 nM), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4-methyl phenyl analogue 9 d (EC₅₀=2.4±0.2 nM, SI=18461) showed broad spectrum HIV inhibitory activity, with EC₅₀ values of 2.4±0.2 nM against wild-type HIV-1, 5.3±0.4 μM against HIV-1 double-mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV-2 ROD strain. Furthermore, structure–activity relationship (SAR) data and molecular modeling results for these compounds are also discussed.

A chiral squaramide catalysts-promoted asymmetric sulfa-Michael conjugated addition of thiols to trans-chalcones is presented. Moderate to excellent yields and high enantioselectivities (up to 99% ee) were achieved under mild conditions.

A concise and efficient asymmetric process for the total synthesis of (20S)-7-ethyl-10-hydroxycamptothecin (=SN-38; 1f), an active metabolic form of the prodrug irinotecan, is described. This approach features the enantioselective cyanosilylation of indolizinone 4 into the corresponding cyanohydrin 5, mediated by a bifunctional thiourea-based cinchona alkaloid under mild conditions, and I₂-catalyzed Friedländer condensation of the tricyclic lactone 6 and 2-amino-5-hydroxy propiophenone (=1-(2-amino-5-hydroxyphenyl)propan-1-one).

The reaction of vinylmagnesium bromide with the (3aS,6aR)-γ-thiolactone 2 in THF afforded, after unexpected ring expansion of the γ-thiolactone moiety, the seven-membered-ring ketone 5 in excellent yield, instead of the expected tertiary alcohol 3.

A series of 38 2-naphthyl-substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV-1 wild-type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild-type HIV-1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild-type HIV-1 with an EC₅₀ value of 0.002 μM and against the double mutant strain with an EC₅₀ value of 0.24 μM; the selectivity index (SI) against wild-type is >180 000, the highest SI value among DAPY analogues. The structure–activity relationship (SAR) of the newly synthesized DAPYs is presented herein.

A practical and asymmetric process for the total synthesis of (+)-biotin (1) has been accomplished starting from cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (2). This approach features a highly enantioselective alcoholysis of meso-cyclic anhydride 3 into (4S,5R)-cinnamyl hemiester 4 mediated by Cinchona alkaloids. Another attractive feature of this synthesis involves the use of recyclable palladium nanoparticles-catalyzed assembly of the 4-carboxybutyl chain at C-4 in (3aS,6aR)-thiolactone 7 employing an improved Fukuyama-type cross-coupling reaction

A six-step asymmetric total synthesis of (20S)-camptothecin (1) has been accomplished in 25% overall yield starting from the known pyridone 3. The key steps in this synthesis are the chemoselective Ni-catalyzed hydrogenation of 3-cyanopyridone 6 to 3-formylpyridone 7 in AcOH/pyridine/H₂O and the Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N-sulfonyloxaziridine into (4′S)-tricyclic hydroxylactone 2.

A series of structurally related 2,5-disubstituted 6-(1-naphthylmethyl)-pyrimidin-4(3H)-ones, compounds 6a–6r, were synthesized and evaluated for their in vitro anti-HIV activities in MT-4 cells. Most of the new compounds investigated showed moderate-to-good activities against wild-type HIV-1, with IC₅₀ values in the range 5.64–0.21 μM. Compound 6d was the most potent congener (IC₅₀=0.21 μM, SI=724) in inhibiting HIV-1 replication, which is ca. 25 times more effective than the reference compound 2′,3′-dideoxyinosine (DDI). Preliminary structure–activity relationship (SAR) studies revealed that both modulation of the amino function at C(2) and of the alkyl group at C(5) of the pyrimidine ring are crucial for high anti-HIV-1 activity.

A practical and highly regio- and stereoselective synthesis of oligoprenols starting from commercially available geraniol is described. The convergent synthetic strategy features the iterative allyl-allyl coupling of monomers easily derived from geraniol that contain one reacting terminal functional group and the repetitive reductive elimination of the p-toluenesulfonyl (Ts) groups.