Synthesis and biological evaluation of histone deacetylase and DNA topoisomerase II-Targeted inhibitors.

HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated. Among the synthesized hybrid compounds, compound 16b showed the potent HDAC inhibitory activity at a low nanomolar level and exhibited antiproliferative activity toward cancer cell lines including MCF-7 (breast), HCT-116 (colon), and DU-145 (prostate) cancer cells at a low micromolar level. Moreover, compound 16a showed HDAC6-selectivity 20-fold over HDAC1.

Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides.

We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration.

Exploration of Dimethylzinc-Mediated Radical Reactions.

In this account, our studies on radical reactions that are promoted by dimethylzinc and air are described. Advantages of this reagent and differences from conventional radical initiators, such as triethylborane, are discussed.

Total synthesis of (+)-trans-dihydronarciclasine utilizing asymmetric conjugate addition.

A highly efficient short-step construction of the common phenanthridine skeleton of pancratistatin-class alkaloids was accomplished in enantiomerically pure form using chiral ligand-controlled asymmetric conjugate addition. The utility of the intermediate was demonstrated by the total synthesis of (+)-trans-dihydronarciclasine with mild oxidation from an amine to an amide as a key step.

General entry to asymmetric one-pot [N + 2 + n] cyclization for the synthesis of three- to seven-membered azacycloalkanes.

Enantio- and diastereoselective one-pot synthesis of three- to seven-membered cis-azaheterocycles was achieved using a triggered asymmetric conjugate addition reaction of lithium amide with an enoate, followed by alkylation of the resulting lithium enolate with α,ω-dihaloalkane and N-alkylation. Isomerization of cis-azaheterocycles with a base yielded the trans-product, constituting a one-pot synthesis of cis-azacycles and a two-step synthesis of trans-azacycles. The four-step asymmetric synthesis of nemonapride highlights the general utility of the method.

Radical one-pot α,ß-dual and ß-mono-oxymethylation of alkylidenemalonate.

Dimethylzinc-mediated radical conjugate addition reaction of dimethyl alkylidenemalonates with iodomethyl pivalate gave a high yield of the α,ß-dual oxymethylation product in one pot under air and the ß-pivaloyloxymethylation product under argon.

High performance of N-alkoxycarbonyl-imines in triethylborane-mediated tin-free radical addition.

Triethylborane-mediated tin-free radical alkylation of N-alkoxycarbonyl-imines, such as N-Boc-, N-Cbz-, and N-Teoc-imines, proceeded smoothly at a low temperature (-78 to -20 °C) to give the corresponding adducts in high yield. Although the formation of isocyanate was the major unfavorable reaction at room temperature, a one-pot conversion of N-Boc-imine to N-ethoxycarbonyl-adduct was possible through the corresponding isocyanate generated in situ. The higher performance of N-alkoxycarbonyl-imine than those of N-Ts- and N-PMP-imines is rationalized by a moderate electron-withdrawing character of an alkoxycarbonyl group that makes both addition of alkyl radical and trapping of the resulting aminyl radical by triethylborane efficiently fast.

Chiral N-heterocyclic carbene-copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides: steric and electronic effects on γ-selectivity.

Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve γ-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High γ-selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed σ-allyl copper intermediate enhance the rate of the reductive elimination to give γ-products as major isomers.

Stereoselective formal synthesis of (+)-allokainic acid via thiol-mediated acyl radical cyclization.

Stereoselective formal synthesis of (+)-allokainic acid was accomplished starting from L-glutamate by using a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly diastereoselective manner to give trans-4,5-disubstituted pyrrolidin-3-one without the production of the cis-isomer. The pyrrolidinone was then converted into the established synthetic intermediate of (+)-allokainic acid via the iron-catalyzed coupling reaction with an isopropenyl Grignard reagent.

Stereoselective radical addition of an acetal to sterically tuned enantiomerically pure N-sulfinyl imines.

Enantiomerically enriched sulfonamides were synthesized by the radical addition of an acetal to enantiomerically pure N-sulfinyl imines using dimethylzinc-air and boron trifluoride diethyl etherate. Higher levels of stereocontrol were observed by using a mesitylenesulfinyl group. Furthermore, an amine and an amino alcohol with high enantiomeric purity were obtainable from the sulfonamide product.

Chiral amidophosphane-rhodium(i)-catalyzed asymmetric conjugate arylation of acyclic enones with arylboronic acids.

A catalytic asymmetric conjugate arylation of acyclic alpha,beta-unsaturated ketones with arylboronic acids was catalyzed by 3 mol% of chiral amidomonophosphane 1-rhodium(I) in the presence of potassium hydroxide in a mixture of 1,4-dioxane and water at 70 degrees C to afford 1,4-conjugate arylated acyclic ketones with high enantiomeric excess in high chemical yield. Thirteen examples of the reaction demonstrate the general applicability of the catalytic system.

Steric tuning of the amidomonophosphane-rhodium(I) catalyst in asymmetric addition of arylboroxines to N-phosphinoyl aldimines.

Highly enantioselective rhodium-catalyzed addition of arylboroxines to N-phosphinoylaldimines was realized by the steric tuning of a diphenylphosphorus moiety to a di(o-tolyl)phosphorus moiety of a chiral amidomonophosphane. The presence of MS 4 A in a 5:1 solvent mixture of dioxane-propanol was essential to afford the corresponding diarylmethylamines in high yield.

Asymmetric construction of binaphthyl by the chiral diether-mediated conjugate addition of naphthyllithium to naphthalenecarboxylic acid 2,6-di-t-butyl-4-methoxyphenyl ester.

Two ways for the synthesis of binaphthyl were examined based on a chiral ligand-mediated asymmetric conjugate addition of 1-naphthyllithium to naththalene-2-carboxylic acid 2,6-di-t-butyl-4-methoxyphenyl esters. The one pot method by conjugate addition-elimination gave a relatively higher enantioselectivity than the two step synthesis based on addition and subsequent oxidative aromatization.

Asymmetric construction of three contiguous stereogenic centers by conjugate addition-alkylation of lithium ester enolate.

A chiral ligand- and lithium amide-assisted asymmetric conjugate addition of lithium enolate of propionate to cyclopentenecarboxylate gave the corresponding lithium enolate, whose allylation gave the key intermediate of the marine alkaloid halichlorine as a single diastereomer with moderate enantioselectivity.

Enantioselective conjugate addition of a lithium ester enolate catalyzed by chiral lithium amides: a possible intermediate characterized.

Two 1:1 noncovalent mixed aggregates between a lithium enolate and two diastereomeric lithium amides have been identified spectroscopically in THF. The NMR data, as well as DFT theoretical calculations, shine some light on a puzzling reversal of induction, observed when switching from one diastereomer of the amide to the other in the enantioselective Michael addition of the lithium enolate to an unsaturated ester.

Total synthesis of (-)-lycorine and (-)-2-epi-lycorine by asymmetric conjugate addition cascade.

Total syntheses of (-)-lycorine and (-)-2-epi-lycorine were accomplished using chiral ligand-controlled asymmetric cascade conjugate addition methodology, which enables the formation of two C-C bonds and three stereogenic centers in one pot to give synthetically useful chiral cyclohexane derivatives.

Asymmetric construction of quaternary carbon centers by sequential conjugate addition of lithium amide and in situ alkylation: utility in the synthesis of (-)-aspidospermidine.

Chiral diether ligand-controlled asymmetric conjugate addition of a lithium amide to cyclopentenecarboxylate and subsequent in situ alkylation gave a chiral cyclopentane derivative bearing a quaternary carbon with high enantio- and diastereoselectivity. The cyclopentane derivative was converted successfully to (-)-aspidospermidine.

Dimethylzinc-initiated radical reactions.

Developments in modern organic synthesis owe much to the field of radical chemistry. Mild reaction conditions, high selectivity, good functional group tolerance and high product yield are features that have made reactions involving radical species indispensable tools for synthetic chemists. In part, the discovery of new radical initiators has led to the efficiency that now characterizes most radical reactions. This Account describes our investigations of radical reactions initiated by dimethylzinc. In 2001, we unexpectedly observed this reaction while investigating the amidophosphane-copper-catalyzed asymmetric addition of dimethylzinc to N-sulfonyl imines with tetrahydrofuran (THF) as reaction solvent. However, instead of adding the desired methyl group to the N-sulfonyl imine, we produced the THF adduct in excellent yield. This result laid the foundation for our discovery of novel modes of reactivity. Further investigations of the unexpected addition reaction revealed that a trace amount of air was needed for reaction progress, indicating that radical intermediates were involved. Indeed, controlled injection of air into the reaction flask by a syringe pump through a sodium hydroxide tube afforded the products in good to excellent yield. In addition, the reaction proved to be chemoselective for a C=N bond over a C=O bond, as well as for 1,4-addition over 1,2-addition. We developed asymmetric variants of the radical addition reaction of ethers to imines using chiral N-sulfinyl imines to produce the adducts in reasonably high stereoselectivity (up to 11:1). A 93:7 diastereomeric ratio of the adduct was obtained when bis(8-phenylmenthyl) benzylidenemalonate was used in the radical addition of ethers to C=C bonds. Interestingly, in the presence of dimethylzinc and air, arylamines, alkoxyamines, and dialkylhydrazines react with THF to give amino alcohols, oximes, and hydrazones, respectively, in moderate to high yields. We performed a tin-free intermolecular addition of functionalized primary alkyl groups, generated from their corresponding iodides, to N-sulfonyl imines using dimethylzinc, air, boron trifluoride diethyl etherate, and a catalytic amount of copper(II) triflate. Direct C-H bond cleavage from cycloalkanes was also feasible in the presence of dimethylzinc, air, and boron trifluoride diethyl etherate to give the corresponding cycloalkyl radicals, which were suitable nucleophiles for N-sulfonyl imines. In all of the above reactions, dimethylzinc was a superior radical initiator than other conventional initiators such as dibenzoyl peroxide, diethylzinc, and triethylborane. We hope the coming decades will witness the report of other novel radical initiators that would complement the reactivity modes of existing ones.