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Peptide alkyl thioesters are versatile reagents in various synthetic applications, commonly generated from peptide hydrazides and thiols. However, a notable limitation is the need for a substantial excess of the thiol reagent, restricting the usage to simple thiols. Here, we introduce an adapted procedure that significantly enhances thioester production with just a minimal thiol excess, facilitating the use of advanced thiol nucleophiles.

An efficient catalytic borylation reaction of aryl bromides in water based on Pd catalysis under micellar conditions is presented. The peculiar combination of the proper Pd precursor with a Sphos ligand and a hindered lipophilic base ensures good yields in the synthesis of a wide range of boronic esters, even for heteroaryl derivatives with a good purity profile. The method is specifically developed for the in situ preparation of boronic esters that are directly converted into examples of relevant active pharmaceutical ingredient intermediates through cross-coupling reactions or via oxidation to phenols.

Fatty acid esters of hydroxy fatty acids (FAHFAs), a newly discovered class of human endogenous complex lipids showing great promise for treating diabetes and inflammatory diseases, exist naturally in extremely low concentrations. This work reports a chemo-enzymatic approach for the comprehensive synthesis of phospholipids containing FAHFAs via sequential steps: hydratase-catalyzed hydration of unsaturated fatty acids to generate structurally diverse hydroxy fatty acids (HFAs), followed by the selective esterification of these HFAs with fatty acids mediated by secondary alcohol-specific Candida antarctica lipase A (CALA), resulting in the formation of a series of diverse FAHFA analogs. The final synthesis is completed through carbodiimide-based coupling of FAHFAs with glycerophosphatidylcholine. Optimal reaction conditions are identified for each step, and the substrate affinity of CALA, responsible for the catalytic mechanisms during FAHFA production, is evaluated through molecular docking. Compared to multistep lab-tedious chemical synthesis, this route, relying on natural building blocks and natural biocatalysts, is significantly facile, scalable, and highly selective, affording high yields (74-98 mol %) in each step for the construction of higher FAHFA-PC series (10/12/13-FAHFAs). The developed strategy aims to increase the availability of naturally occurring FAHFA species and provide the tools for the construction of versatile and novel analogs of FAHFA conjugates.

Herein, we present a novel method for the N -arylation of amino acid esters using α-bromoacetaldehyde acetal and acetoacetate via an I 2 -mediated metal-free benzannulation strategy, which disclosed the first synthetic application of N -arylation of amino acids using nonaromatic building blocks. The synthesized N -arylated amino acid derivatives were found to possess promising selective inhibition against human hepatocellular liver carcinoma cells, human melanoma cells, and human normal liver cells, with an IC 50 value as low as 16.79 μg·mL -1 .

A detailed theoretical mechanistic investigation on the dynamic kinetic resolution of N-protected amino acid esters using phase-transfer catalysts is described. Semiautomatic exhaustive conformation search of transition state (TS)-like structures were carried out using the ConFinder program and the pseudo-TS conformational search (PTSCS) method. This conformational search method successfully provided reasonable TS structures for determining the stereoselectivity in the asymmetric base hydrolysis of hexafluoroisopropyl (HFIP) esters as well as the racemization mechanism. Furthermore, the independent gradient model (IGM) analysis of the TS structures suggested that the H-bonding interactions with the oxyanion hole and π-stacking interactions are the common important features of the proposed TS structures that determine the stereoselectivity.

Palladium-catalyzed Suzuki reactions of brominated flavin derivatives (5-deazaflavins, alloxazines, and isoalloxazines) with boronic acids or boronic acid esters that occur readily under mild conditions were shown to be an effective tool for the synthesis of a broad range of 7/8-arylflavins. In general, the introduction of an aryl/heteroaryl group by means of a direct C-C bond has been shown to be a promising approach to tuning the photophysical properties of flavin derivatives. The aryl substituents caused a bathochromic shift in the absorption spectra of up to 52 nm and prolonged the fluorescence lifetime by up to 1 order of magnitude. Moreover, arylation of flavin derivatives decreased their ability to generate singlet oxygen.

We report palladium-catalyzed aminocarbonylation of (hetero)aryl iodides with α-amino acid esters as nucleophiles. The synthesized N-capped α-amino acids are biologically important building blocks. The mild conditions provide products with high enantioselectivity at 80 °C in 35 min. The reactions are performed under air in a sealed vessel using chloroform as an in situ CO source. For the first time, regioselective carbonylation of histidine is also presented.

A new chemistry of azo compounds, that is, addition of free radicals generated in situ to access various acyl hydrazides, has been developed. The protocol provides a novel strategy for the synthesis of valuable acyl hydrazides. The transformation features mild reaction conditions, good tolerance of functional groups, and a broad substrate scope. In view of the importance of acyl hydrazides in functional materials and medicinal chemistry, this approach would find broad applications.

Herein, a new strategy for the synthesis of monofluoroalkenes via employing α-fluoroacrylic acids and N -hydroxyphthalimide (NHPI) redox-active esters as coupling partners has been developed. This decarboxylative reaction enabled the formation of C(sp 2 )-C(sp 3 ) bonds to provide a practical and efficient approach for the construction of a variety of monofluoroalkenes, which are key structural motifs in organic chemistry, under mild reaction conditions. The protocol exhibited excellent functional group compatibility and delivered monofluoroalkene products with excellent Z -stereoselectivity. This work also provides a platform for the modification of complex biologically active molecules containing carboxylic acids.

We report a general, scalable, and convenient photochemical process for diversities of distal oxygenated nitriles from corresponding less-strained ketoxime esters allowing one-step introductions of ether and cyano groups, which avoids the utilization of toxic cyanide reagents. A wide range of ketoxime esters involving five-membered to eight-membered cycloketoxime esters and linear ketoxime esters participate smoothly under operately simple and mild conditions, affording structurally variable ring-opening products.

Ubiquitin (Ub)-based fluorescent reagents are crucial to explore the activity of deubiquitinases (DUBs). Ub-Rho110-G is one of the preferred tools, whereas the current synthetic route is time-consuming. Here, we report a new semisynthetic strategy to produce Ub-Rho110-G through direct aminolysis of Boc-protected Ub-Mesna using bisglycyl-rhodamine 110. We also applied this strategy to synthesize active SUMO2-Rho110-G for the first time. Biochemical analysis demonstrated that semisynthetic Ub or SUMO-Rho110-G can be effectively used for the detection of the activity of DUBs or SUMO-specific enzymes.

A general AzePhenol dinuclear zinc catalytic system has been successfully developed and applied into the asymmetric Michael addition of 4-hydroxyl pyrones and 4-hydroxycoumarins to β,γ-unsaturated α-keto esters. Excellent yields (up to 99%) and high enantioselectivities (up to 94% ee) are obtained for a wide range of substrates under mild conditions in the absence of additives. This bimetallic catalytic approach represents a new and effective asymmetric synthetic protocol to access a variety of bioactive compounds with pharmacological interest. The possible mechanism is proposed to explain the origin of the asymmetric induction.

A regio- and diastereoselective conjugate addition of the lithium anion of N-allyl imine (prepared from allylamine and benzophenone) to α,β-unsaturated esters in good yields is reported. The reaction was general and provided the γ-amino esters resulting from the regioselective C-C bond formation between the α-carbon to the nitrogen in the imine and the β-carbon of the unsaturated ester. Synthetic utility of the formed products was illustrated in the nonracemic total synthesis of the bioactive alkaloid (-)-epibatidine.

Trichloroacetimidates are useful reagents for the synthesis of esters under mild conditions that do not require an exogenous promoter. These conditions avoid the undesired decomposition of substrates with sensitive functional groups that are often observed with the use of strong Lewis or Brønsted acids. With heating, these reactions have been extended to benzyl esters without electron-donating groups. These inexpensive and convenient methods should find application in the formation of esters in complex substrates.

Amiaspochalasins A-H (1-8), eight undescribed aspochalasins, and trichalasin D (9), a known analogue, were isolated from the solid culture of Aspergillus micronesiensis. Compounds 1-9 are aspochalasins with a C-21 ester carbonyl, and their structures were determined by spectroscopic data, X-ray crystallographic analyses, electronic circular dichroism calculations, and chemical methods. The CH 3 -25 in compound 1 is located at C-16 rather than C-14 in the previously reported aspochalasins, endowing 1 with an unexpected carbon skeleton. Compounds 2 and 3 are the first examples of aspochalasins with an unprecedented 5/6/6/8 tetracyclic ring system. Compounds 4 and 5 are diastereomers of aspochalasins I and J, respectively. Compounds 6 and 7 are the first aspochalasins featuring a long open-chain system, and their absolute configurations were discussed by comparing the NMR data of the hydrolysis and methyl esterification products of 4 and 5. Compound 8 is an isomeride of 9. The cytotoxic and antimicrobial effects of 1-9 were tested.

A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Owing to the pervasiveness of hydroxyl groups in natural isolates, alcohol derivatives are alluring directing groups. Herein, an alcohol-derived sulfamate ester guides the light-initiated xanthylation of primary, secondary, or tertiary centers. This process enables formal directed deuteration, azidation, thiolation, and vinylation reactions.

Enabled by the discovery of new cinchonium salts and coadditives, a direct and efficient asymmetric access to trifluoromethylated γ-amino esters/lactones has been realized through the enantioselective and diastereoselective umpolung reaction of trifluoromethyl imines with acrylates or α,β-unsaturated lactones as carbon electrophiles. At 0.5-5.0 mol % catalyst loadings, the newly developed catalytic system activates a variety of imine substrates as unconventional nucleophiles to mediate highly chemo-, regio-, diastereo-, and enantioselective C-C bond forming reactions. The developed synthetic protocol represents an excellent strategy to target a series of versatile and enantiomerically enriched γ-amino esters/lactones in good to excellent yields from the readily available starting materials. Additionally, we found that the epi-vinyl catalysts based on cinchonidine and quinine promote a similarly high enantioselective reaction generating the opposite configuration of chiral products in a highly efficient manner, which allows convenient access to either the R- or S-enantiomer of the chiral amine products in high yields and excellent enantioselectivities.

Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome.

An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem-diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters.

Bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides undergo alternating ring-opening metathesis polymerization (AROMP) with cyclohexene. Herein, a general method for the preparation of bicyclo[4.2.0]oct-(8)-ene-8-carboxy derivatives is described. The central 8-cyano intermediate provides entry to five different functional group substituents on the alkene. These monomers were tested as potential substrates for AROMP with cyclohexene. In addition to the carboxamide, the carboxynitrile and carboxaldehyde are also substrates for AROMP. In the case of the carboxaldehyde, the polymer is regioregular. However, the addition of carboxynitrile is stereoirregular and slow.

New fluorous enantiopure (S)-α-aminated β-keto esters were prepared through a highly enantioselective electrophilic α-amination step in the presence of europium triflate and (R,R)-phenyl-pybox. These compounds are precursors of fluorinated analogues of l-carbidopa, which is known to inhibit DOPA decarboxylase (DDC), a key protein in Parkinson's disease. Fluorination provides better stability for biological applications, which could possibly lead to DDC inhibitors better than l-carbidopa itself. Induced fit docking computational simulations performed on the new structures interacting with DDC highlight that for an efficient binding at the DDC site, at least one hydroxyl substituent must be present at the aromatic ring of the l-carbidopa analogues and show that the presence of fluorine can further fix the position of the ligand in the active site.

Esters are valuable electrophiles for cross-coupling due to their ubiquity and ease of synthesis. However, harsh conditions are traditionally required for the effective cross-coupling of ester substrates. Utilizing a recently discovered precatalyst, Pd-catalyzed Suzuki-Miyaura and Buchwald-Hartwig reactions involving cleavage of the C(acyl)-O bond of aryl esters that proceed under mild conditions are reported. The Pd(II) precatalyst is highly active because it is reduced to the Pd(0) active species more rapidly than previous precatalysts.

The synthesis of the A-B-cis,B-C-trans-annulated cyclohepta[e]hydrindane core of a gagunin E analogue is reported in detail. The tricarbocyclic scaffold was assembled starting from an easily accessible A ring building block by a (4 + 2)-cycloaddition for annulation of the B ring. A ring-closing metathesis served for construction of the seven-membered C ring. The angular methyl groups were attached by electrophilic cyclopropanation-ring opening. A library based on the most active lead compound was made accessible by esterification of the terpenols with commercially available acids. A transannular etherification reaction gave access to tetracyclic derivatives of the synthetic inhibitors. The members of the compound library of non-natural homoverrucosanoid-derived esters were examined as modulators of the membrane transporter proteins ABCB1 (P-gp), ABCG2 (BCRP), and ABCC1 (MRP1), which are involved in the formation of multidrug resistance (MDR) in cancer chemotherapy.

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components' condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an S N 1-like (S N 2C+) mechanism in which nucleophiles add to the iminium-chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.

A mild, practical, and simple procedure for phenyl selenoesters synthesis from several anhydrides and diphenyl diselenide was developed. This transition-metal-free method provides a straightforward entry to storable Fmoc-amino acid selenoesters which are effective chemoselective acylating reagents. An application to oligopeptide synthesis was illustrated.

A quinidine-catalyzed diastereoselective addition of α-angelica lactone to β-halo-α-ketoesters is reported. The α-angelica lactone displays unusual regioselectivity in this reaction, acting as a nucleophile at the α-position to provide fully substituted glycolic esters with three contiguous stereocenters. Subsequent diastereoselective hydrogenation provides an additional stereocenter within the lactone.

Total syntheses of five naturally occurring polyacetylenes from three different plants are described. These natural products have in common an E,Z-configured conjugated diene linked to a di- or triyne chain. As the key method to stereoselectively establish the E,Z-diene part, an ester-tethered ring-closing metathesis/base-induced eliminative ring opening sequence was used. The results presented herein do not only showcase the utility of this tethered RCM variant but have also prompted us to suggest that the originally assigned absolute configurations of chiral polyacetylenes from Atractylodes macrocephala should be revised or at least reconsidered.

The use of bulky Lewis acids, aluminum tris(2,6-diphenylphenoxide) (ATPH) and aluminum tris(2,6-di-2-naphthylphenoxide) (ATNP), in the doubly vinylogous aldol reaction between methyl-5-methyl-2-furoate and aldehydes or ketones is described. These reactions proceed smoothly and in high yields with both enolizable and non-enolizable substrates. This C-C bond-forming reaction enables a new bond construction for the synthesis of functionalized furans.

Previous studies have demonstrated that amidic α/β-pseudodipeptides, 1:1 [α/α-N α -Bn-hydrazino], have the ability to fold via a succession of γ-turn (C 7 pseudocycle) and hydrazinoturn in CDCl 3 solution, their amide terminals enabling the formation of an intramolecular H-bond network. Despite their lack of a primary amide terminals allowing the formation of the hydrazinoturn, their ester counterparts 1-4 were proven to self-assemble into C 6 and C 7 pseudocycles by intramolecular H-bonds in solution state and into an uncommon twisted parallel β-sheet through intermolecular H-bonding in the crystal state to form a supramolecular helix, with eight molecules needed to complete a full 360° rotation. Such self-organization (with eight molecules) has only been observed in a specific α/α-pseudodipeptide, depsipeptide (Boc-Leu-Lac-OEt). Relying on IR absorption, NMR, X-ray diffraction, and CD analyses, the aim of this study was to demonstrate that stereoisomers of ester 1:1 [α/α-N α -Bn-hydrazino] pseudodipeptides 1-4 are able to self-assemble into this β-helical structure. The absolute configuration of the asymmetric C α -atom of the α-amino acid residue influences the left- or right-handed twist without changing the pitch of the formed helix.

Osmium(0) complexes derived from Os3(CO)12 and XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) catalyze the C-C coupling of α-hydroxy esters 1a-1i, α-ketols 1j-1o, or 1,2-diols dihydro-1j-1o with ethylene 2a to form ethylated tertiary alcohols 3a-3o. As illustrated in couplings of 1-octene 2b with vicinally dioxygenated reactants 1a, 1b, 1i, 1j, 1k, 1m, higher α-olefins are converted to adducts 4a, 4b, 4i, 4j, 4k, 4m with complete levels of branched regioselectivity. Oxidation level independent C-C coupling is demonstrated by the reaction of 1-octene 2b with diol dihydro-1k, α-ketol 1k, and dione dehydro-1k. Functionalized olefins 2c-2f react with ethyl mandelate 1a to furnish adducts 5a-8a as single regioisomers. The collective data, including deuterium labeling studies, are consistent with a catalytic mechanism involving olefin-dione oxidative coupling to form an oxa-osmacyclopentane, which upon reductive cleavage via hydrogen transfer from the secondary alcohol reactant releases the product of carbinol C-alkylation with regeneration of the ketone. Single-crystal X-ray diffraction data of the dinuclear complex Os2(CO)4(O2CR)2(XPhos)2 and the trinuclear complex Os3(CO)11(XPhos) are reported. These studies suggest increased π-backbonding at the stage of the metal-olefin π-complex plays a critical role in facilitating alkene-carbonyl oxidative coupling, as isostructural ruthenium(0) complexes, which are weaker π-donors, do not catalyze the transformations reported herein.

The cyclopenta[b]indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta[b]indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita-Baylis-Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding β-hydroxy-esters. The diastereoisomeric mixture was then treated with a catalytic amount of triflic acid (20 mol %) to give cyclopenta[b]indoles with overall yields ranging from 8 to 73% (for 2 steps). The acid-catalyzed cyclization step gave the required heterocycles, via an intramolecular Friedel-Crafts reaction, with high diastereoselectivity, where only the trans product was observed. A mechanistic study monitored by ESI-(+)-MS was also conducted to collect evidence about the mechanism of this reaction. The new molecules herein synthesized were also evaluated against a panel of human cancer cells demonstrating a promising antitumoral profile.

The preparation of a series of mannopyranosyl donors carrying 2-O-(2-oxoalkyl) ethers and their use in glycosylation reactions are described. The formation of cyclic products with the simple 2-O-phenacyl ether and with the 2-O-(t-butoxycarbonylmethyl) ether establishes the stereoelectronic feasibility of participation in such systems. The high β-selectivities observed with the bis-trifluoromethyl phenacyl ether indicate that participation can be suppressed through the introduction of electron-withdrawing substituents. The high β-selectivities and absence of cyclic products observed with the 2-O-(methoxycarbonylmethyl) ether exclude the effective participation of esters through six-membered cyclic intermediates in this series. The results are discussed in terms of the conformation of cyclic dioxenium ions (E,E-, E,Z-, or Z,Z-) and in the context of "neighboring group" participation by nonvicinal esters in glycosylation. Methods for the deprotection of the 2-O-phenacyl and 2-O-(methoxycarbonylmethyl) ethers are described.

Pyrrolidine-2-carboxylate esters substituted in the 3-, 4- or 5-positions were converted to their N'-aryl urea derivatives. Deprotonation at the 2-position to form a potassium enolate led to migration of the N'-aryl substituent to the 2 position of the pyrrolidine ring, followed by cyclization of the resulting urea to give bicyclic α-aryl hydantoin derivatives of substituted prolines. Depending on the substitution pattern of the starting material, high diastereoselectivity was observed in the aryl migration, allowing formation of the products in enantiomerically enriched form, despite the intermediacy of a planar enolate. The hydrolysis of the bicyclic hydantoins under basic conditions gave a range of enantiopure and enantioenriched quaternary α-aryl proline derivatives.

Facile synthesis of a variety of α-heterosubstituted ketones under mild conditions was achieved by copper-mediated cross-coupling of thioesters with functionalized organostannanes. Application of this coupling methodology provided a concise pathway for the conversion of carboxylic acids to 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles via thioesters in practical yields.

A highly regioselective palladium-catalyzed ester-directed ortho-olefination of phenyl acetic and propionic esters with olefins via C-H bond activation has been developed. A wide variety of phenyl acetic and propionic esters were tolerated in this transformation, affording the corresponding olefinated aromatic compounds. The ortho-olefination of heterocyclic acetic and propionic esters also took place smoothly giving the products in good yields, thus proving the potential utility of this protocol in synthetic chemistry.

Homochiral methyl 4-aminopyrrolidine-2-carboxylates are readily obtained by means of asymmetric (3 + 2) cycloadditions between azomethine ylides and nitroalkenes, followed by catalytic hydrogenation of the intermediate 4-nitro cycloadducts. These 4-aminopyrrolidine-2-carboxylate esters belong to the L-series of natural amino acids and catalyze asymmetric Michael additions of ketones to nitroalkenes. However, the enantioselectivity observed with these novel unnatural organocatalysts is opposite to that obtained with L-proline. Since both 4-nitro and 4-amino L-proline esters are efficient organocatalysts of aldol reactions, these results permit to modulate asymmetric quimioselective aldol and conjugate addition reactions.

A series of amphiphilic ligands were designed and synthesized. The rhodium complexes with the ligands were applied to the asymmetric transfer hydrogenation of broad range of long-chained aliphatic ketoesters in neat water. Quantitative conversion and excellent enantioselectivity (up to 99% ee) was observed for α-, β-, γ-, δ- and ε-ketoesters as well as for α- and β-acyloxyketone using chiral surfactant-type catalyst 2. The CH/π interaction and the strong hydrophobic interaction of long aliphatic chains between the catalyst and the substrate in the metallomicelle core played a key role in the catalytic transition state. Synergistic effects between the metal-catalyzed site and the hydrophobic microenvironment of the core in the micelle contributed to high stereoselectivity.

The potential of β,γ-unsaturated α-ketothioesters participating in hetero-Diels-Alder reaction has remained unexplored. We report herein the first study of a ZnI2-catalyzed highly diastereoselective inverse electron demand hetero-Diels-Alder reaction of β,γ-unsaturated α-ketothioesters with olefins to access highly substituted 3,4-dihydro-2H-pyrans. All the reactions proceed with cis-selectivity in moderate to excellent yields. Under similar reaction conditions, terminal alkynes undergo direct conjugate 1,4-addition to yield δ,ε-acetylenic α-ketothioesters. Furthermore, the utility of these cycloadducts has been demonstrated by an NBS-MeOH mediated stereospecific efficient access to fully substituted pyran rings. The product bromoethers undergo E2 elimination with DBU, resulting in substituted 3,6-dihydro-2H-pyrans. In addition, the thioester moiety of the products has been used for further transformations, such as amidations and Fukuyama coupling reactions.

In continuation of our previous study on the intramolecular reductive coupling of simple homoallylic esters promoted by allylSmBr/HMPA/H2O, which afforded a facile synthesis of 2-(2-hydroxyalkyl)cyclopropanols, here we report the reductive cascade cyclization of but-3-enyl but-3-enoates mediated by allylSmBr/HMPA/CuCl2·2H2O, in which the two C═C bonds were successively coupled to allow the construction of the structurally interesting bridged bicyclic tertiary alcohols. Thus, the 2-(2-hydroxyethyl)bicyclo[2.1.1]hexan-1-ols were prepared in moderate to good yields with excellent diastereoselectivity.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push-pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

The Candida antarctica lipase B (CAL-B) catalyzed kinetic resolution of primary and secondary alcohols via acetylation is dependent on the permittivity (ε) of the reaction solvent. For example, the enantiomeric ratio (E) vs ε plot for the acetylation of 1-(naphth-2-yl)ethanol (1) exhibits a convex shape, taking the maximum E value at a medium ε value (11.2), whereas the same plot for the acetylation of benzyl 3-hydroxybutylate (3) exhibits a concave shape, taking the minimum E value at a similar ε value (11.6). Kinetic studies reveal that the difference in shape of the E vs ε plots originates from the relative reaction rate between the enantiomers with different Michaelis constants (Km). Thus, when the enantiomer with a larger Km value in the middle ε region reacts more slowly than its antipode, the ε dependence of E exhibits a convex shape. On the other hand, when the enantiomer reacts more quickly, it exhibits a concave shape. The E vs ε plot for the acetylation of 2-methoxy-2-phenylethanol (7) exhibits a convex shape with the maximum E value (20) at ε = 14.1. The E value can be further improved to almost reach the efficiency required for industrial applications (E ≈ 30) by the addition of a nitro compound.

Catalyzed by supported gold nanoparticles, an aminolysis reaction between various aryl esters and inert tertiary amines by C-O and C-N bond activations has been developed for the selective synthesis of tertiary amides. Comparison studies indicated that the gold nanoparticles could perform energy-efficient green catalysis at room temperature, whereas Pd(OAc)2 could not.

Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.

Ab initio asymmetric syntheses of methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide, employing diastereoselective epoxidation and dihydroxylation, respectively, of alkyl (3S,αR,Z)-3-[N-benzyl-N-(α-methylbenzyl)amino]hex-4-enoates as the key steps, are reported. The requisite substrates were readily prepared using the conjugate additions of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl and tert-butyl (E)-hexa-2-en-4-ynoates followed by diastereoselective alkyne reduction. syn-Dihydroxylation using OsO4 proceeded under steric control on the 4Re,5Re face of the olefin to give the corresponding diol, which subsequently underwent lactonization. Meanwhile, epoxidation using F3CCO3H in conjunction with F3CCO2H proceeded on the opposite 4Si,5Si face of the olefin under hydrogen-bonding control from the in situ formed ammonium ion. Treatment of the intermediate epoxide with concd aq H2SO4 promoted highly regioselective ring-opening (distal to the in situ formed ammonium moiety) to give the corresponding diol (completing overall the formal anti-dihydroxylation of the olefin), which then underwent lactonization under the reaction conditions. Elaboration of these diastereoisomeric lactones through hydrogenolysis, N-Boc protection, reduction, methanolysis, and acetate protection gave methyl N,O-diacetyl-D-3-epi-daunosaminide and methyl N,O-diacetyl-D-ristosaminide.

Metal alkoxides, such as NaOt-Bu or Ti(OBu)4, can initiate acyl exchange within complex ester libraries. Reactive distillation of such dynamic combinatorial libraries (DCLs) isolates the most volatile ester at the expense of the less volatile library members that share a constituent with it. This process can be iteratively repeated to yield up to four industrially relevant esters as pure products from a single reaction setup. An algorithm has been developed to predict reactive distillation products in DCLs of as many as 121 members.

CF3-containing esters smoothly reacted with electron-deficient alkenes in the presence of a phosphine (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) organocatalyst at room temperature in an aerobic atmosphere. These Michael reactions efficiently provided products with a CF3 quaternary carbon center.

Formylthiocholine (FTC) was synthesized and found to be a substrate for nonenzymatic and butyrylcholinesterase (BChE)-catalyzed hydrolysis. Solvent (D2O) and secondary formyl-H kinetic isotope effects (KIEs) were measured by an NMR spectroscopic method. The solvent (D2O) KIEs are (D2O)k = 0.20 in 200 mM HCl, (D2O)k = 0.81 in 50 mM HCl, and (D2O)k = 4.2 in pure water. The formyl-H KIEs are (D)k = 0.80 in 200 mM HCl, (D)k = 0.77 in 50 mM HCl, (D)k = 0.75 in pure water, (D)k = 0.88 in 50 mM NaOH, and (D)(V/K) = 0.89 in the BChE-catalyzed hydrolysis in MES buffer at pH 6.8. Positional isotope exchange experiments showed no detectable exchange of (18)O into the carbonyl oxygen of FTC or the product, formate, under any of the above conditions. Solvent nucleophile-O KIEs were determined to be (18)k = 0.9917 under neutral conditions, (18)k = 1.0290 (water nucleophile) or (18)k = 0.989 (hydroxide nucleophile) under alkaline conditions, and (18)(V/K) = 0.9925 for BChE catalysis. The acidic, neutral, and BChE-catalyzed reactions are explained in terms of a stepwise mechanism with tetrahedral intermediates. Evidence for a change to a direct displacement mechanism under alkaline conditions is presented.

Aryl boronic acids or pinacol esters containing EDG were converted in good yields and fast reactions to the corresponding aryl fluorides using the readily obtainable solutions of AcOF. In reactions with aryl boronic acids containing EWG at the para position, there are two competing forces: one directing the fluorination to take place ortho to the boronic acid and the other, toward an ipso substitution. With EWG meta to the boronic acid, substitution ipso to the boron moiety takes place in good yields.

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.