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The Ferrier rearrangement was utilized to obtain 2,3-unsaturated diosgenyl glycosides. This reaction proceeded with high stereoselectivity, yielding mostly saponins with an α configuration (hexoses) or predominantly with a β configuration (pentoses). The diversity of the glycals used and the glycosides obtained enabled a deep discussion of the Ferrier rearrangement mechanism. The mechanism was supported by DFT calculations concerning the intermediate ions. It was concluded that the vinylogous anomeric effect may influence the reactivity of the glycals. Two possible Ferrier rearrangement intermediates, dioxolenium and allyloxycarbenium ions, were hypothesized to exist in thermodynamic equilibrium that shifted toward the former. The allyloxycarbenium ion participates in the final rearrangement step and determines the reaction regioselectivity. Furthermore, the conformational stability of the 2,3-unsaturated pyranose ring determines the stereoselectivity of the reaction. Factors influencing this stability, as well as the NMR data enabling recognition of the 0 H 5 and 5 H 0 conformations, were identified. Chemoselective hydrogenation of 2,3-unsaturated diosgenyl glycosides provided a series of 2,3-dideoxy analogues. The anticancer, hemolytic, and antibacterial activities of the synthesized saponins are presented alongside a discussion of the structure-activity relationships.

The unusual d-l-l-d-d-l-l pattern of stereochemistry in residues 1-7 of the peptide antibiotic teixobactin is critical to its extraordinary antibiotic activity, creating an unusual amphiphilic β-sheetlike structure that is essential to its mechanism of action. The current study sought to replace the three d-amino acids in the tail with l-amino acids while maintaining amphiphilicity. We find that swapping residues d-Gln 4 and d- allo -Ile 5 in O -acyl isopeptide prodrugs of teixobactin permits the introduction of l-stereochemistry with retention of antibiotic activity. Nevertheless, modifying the N -terminal stereochemistry results in a loss of antibiotic activity.

We have developed a high yielding synthesis of indolizine and directly elaborated the molecule into three optically active indolizinylalanine regioisomers. The protocols exploit metal catalyzed coupling of indolizinyl-halides with organozinc reagents derived from carbamoylated iodoalanine esters. The scalable protocols provide products in a form amenable to solid-phase peptide synthesis (SPPS). When incorporated into peptides, the indolizine heterocycle is more basic and markedly less nucleophilic than tryptophan. Its protonated vinylpyridinium form is deeply colored in solution while the neutral heterocycle is highly fluorescent. The fluorescence quantum yield of indolizine exceeds that of indole and aza-indoles in water, suggesting that indolizinylalanines could be powerful optical probes of protein structure and dynamics, functioning as true tryptophan isosteres.

Efficient protecting group strategies are important for glycan synthesis and represent a unique synthetic challenge in differentiating sugar ring hydroxyl groups. Direct methods to enable regioselective protecting group installation are thus desirable. Herein, we explore a one-step regioselective benzoylation to deliver 2,3,6-protected d-galactose building blocks from tetrols across a variety of α- and β-, O - and S -glycoside substrates. We focus on benzoyl chloride as the esterifying reagent and a reaction temperature of -40 °C to screen the regioselectivity outcome for twenty-two different glycosides, based on isolated yields. Using this methodology, we demonstrate the capability for α-linked aryl and alkyl glycosides ( O - and S - d-galactosides, d-galactosamines, and l-fucose), delivering consistent isolated yields (>65%) for 2,3,6-benzoylated products. We extend to explore β-linked systems, where the observed regioselectivity is not paralleled. We posit that both steric and electronic factors from the anomeric substituent contribute to modulating the reactivity competition between 2-OH and 4-OH, enabling the formation of regioisomeric mixtures. However, a certain balance of these factors within the aglycon can deliver 2,3,6-regioselectivity, notably for β-O -Et and β-O -CH 2 CF 3 glycosides. The methodology contributes toward understanding the peculiarities of regioselective carbohydrate-protecting group installation, exploring the importance of the anomeric substituent upon ring hydroxyl group reactivity.

(±)-Salvicatone A ( 1 ), a C 27 -meroterpenoid featuring a unique 6/6/6/6/6-pentacyclic carbon skeleton with a 7,8,8a,9,10,10a-hexahydropyren-1 ( 6H )-one motif, was isolated from the roots and rhizomes of Salvia castanea Diels f. tomentosa Stib. Its structure was characterized by comprehensive spectroscopic analyses along with computer-assisted structure elucidation, including ACD/structure elucidator and quantum chemical calculations with 1 H/ 13 C NMR and electronic circular dichroism. Biogenetically, compound 1 was constructed from decarboxylation following [4 + 2] Diels-Alder cycloaddition reaction between caffeic acid and miltirone analogue. Bioassays showed that (-)- 1 and (+)- 1 inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophage cells with an IC 50 value of 6.48 ± 1.25 and 15.76 ± 5.55 μM, respectively. The structure-based virtual screening based on the pharmacophores in ePharmaLib, as well as the molecular docking and molecular dynamics simulations study, implied that (-)- 1 and (+)- 1 may potentially bind to retinoic acid receptor-related orphan receptor C to exert anti-inflammatory activities.

Total syntheses of the title prenylated indole alkaloids together with seven others are reported. Biogenetic considerations have been employed in devising the reaction sequences leading to these targets with, in the opening stages, electrochemically-derived indole-3-carboxaldehyde 15 being subject to an aldol-type condensation reaction involving diketopiperazine derivative 19 . This led, after prototopic shifts, intramolecular Diels-Alder cycloaddition and hydrolysis/deprotection steps, to the racemic forms of the bicyclo[2.2.2]diazaoctane-containing natural product stephacidin A ( 2 ) and its C6 epimer 3 . Epoxidation of the last compound afforded, following rearrangement of the primary oxidation products, a mixture of (±)-taichunamide A [(±)- 4 ] and (±)-versicolamide B [(±)- 7 ]. Related protocols allowed for the conversion of (±)-stephacidin A [(±)- 2 ] into (±)-notoamide B [(±)- 5 ]. Analogous aldol condensation, nucleophilic reduction, and epoxidation steps led to the formation of (-)-notoamide E and its conversion into notoamide C as well as the indole fragmentation product amoenamide E. A late-stage chlorination reaction applied to (±)-stephacidin A provided access to the spirocyclic oxindole (±)-notoamide N [(±)- 6 ].

Our laboratory reported the chemical synthesis and stereochemical assignment of the recently discovered peptide antibiotic clovibactin. The current paper reports an improved, gram-scale synthesis of the amino acid building block Fmoc-(2 R ,3 R )-3-hydroxyasparagine-OH that enables structure-activity relationship studies of clovibactin. An alanine scan reveals that residues Phe 1 , d-Leu 2 , Ser 4 , Leu 7 , and Leu 8 are important for antibiotic activity. The side-chain amide group of the rare d-Hyn 5 residue is not essential to activity and can be replaced with a methyl group with a moderate loss of activity. An acyclic clovibactin analogue reveals that the macrolactone ring is essential to antibiotic activity. The enantiomer of clovibactin is active, albeit somewhat less so than clovibactin. A conformationally constrained clovibactin analogue retains moderate antibiotic activity, while a backbone N -methylated analogue is almost completely inactive. X-ray crystallography of these two analogues reveals that the macrolactone ring adopts a crown-like conformation that binds anions.

We describe the convergent total syntheses of strasseriolides A and B, which are potent antimalarial agents recently isolated from an unnamed plant found in a remote region of New Zealand. Both natural products exhibited potent activity against malaria parasite, Plasmodium falciparum . The synthesis involved asymmetric syn-aldol, asymmetric alkylation, and asymmetric Johnson-Claisen rearrangement to set six of the seven chiral centers of strasseriolide B. The synthesis also highlights the formation of an 18-membered macrolactone from a diacid by using a Yamaguchi macrolactonization protocol. Other key transformations involved Grubbs' cross-metathesis, selective 1,4-reduction, hydrostannylation reaction, and NHK coupling reaction. The convergent synthesis of strasseriolide A required 27 total synthetic steps and 16 longest linear steps from known readily available intermediates.

Codeine and morphine are among the few natural products that are used directly as drugs for medical treatment. However, the availability of these is widely dependent on natural resources. Herein, we report an efficient enantioselective seven-step synthesis of (-)-codeine starting from simpler starting materials. The key steps involve microwave-assisted intramolecular cascade double heck cyclization to access the ABCE ring of opium alkaloids with the required stereocenters in one pot. A photoinduced intramolecular hydroamination of carboxamide forms the D ring and completes the pentacyclic core of the morphinans. Following that, an oxidation followed by global reduction leads to the formation of (-)-codeine. Our synthesis relies on simple and classical reactions to address the opium alkaloids and will serve as an efficient route to access the other morphinans.

We report a streamlined synthesis of (2 S ,3 R ,4 R )-4,5-dihydroxy isoleucine (DHIle), an amino acid found in α-amanitin, which appears to be critical for toxicity. This synthetic route is transition metal-free and enables the production of significant quantities of DHIle with suitable protection for use in peptide synthesis. Its incorporation into a cytotoxic amatoxin analog is reported.

Melibiosamine (Gal-α(1,6)-GlcNH 2 ), consisting of galactose and glucosamine linked by an α(1,6)-glycosidic bond, is an artificial disaccharide derivative that selectively inhibits the proliferation of K562 tumor cells relative to HUC-F2 normal cells. In this study, we employed a linkage-editing strategy to synthesize CH 2 - and CHF-linked melibiosamine analogs through chemo- and stereoselective hydrogenation of fluorovinyl- C -glycoside. ( R )-CHF-Melibiosamine exhibited more potent antiproliferative activity than O -linked melibiosamine, while ( S )-CHF-melibiosamine was less potent.

Divergent total syntheses of binding pocket and peripherally modified tetrachlorovancomycins, a non-native synthetic glycopeptide, and their evaluation are disclosed. Central to the approach is the synthesis of a single late-stage intermediate that bears a residue 4 thioamide ([Ψ[C(═S)NH]Tpg 4 ]tetrachlorovancomycin ( 3 ), LLS 15 steps, 14% overall) as a precursor to either of two key pocket modifications and their pairing with any combination of two peripheral modifications conducted without protecting groups. A stereochemical simplification achieved by the addition of two aryl chlorides removes two synthetically challenging atropisomer centers in native glycopeptides and streamlines the synthesis. Key features include in a convergent epimerization-free thioacylation of the AB ring system amine with an N -thioacylbenzotriazolyl DE tetrapeptide (85%) followed by simultaneous room-temperature S N Ar macrocyclizations of the CD and DE ring systems (96%). The approach provided 3 from which [Ψ[C(═N)NH]Tpg 4 ]tetrachlorovancomycin ( 4 ) and [Ψ(CH 2 NH)Tpg 4 ]tetrachlorovancomycin ( 5 ) were prepared in a single-step and bear binding pocket modifications that convey dual d-Ala-d-Ala/d-Lac ligand binding to overcome vancomycin resistance. The newest maxamycin members are disclosed, bearing two additional peripheral modifications that introduce two independent synergistic MOAs that do not rely on native ligand binding for activity. Ligand binding properties of pocket-modified tetrachlorovancomycins 3 - 5 , antibacterial activity of a key compound series, and PK assessments of two tetrachloromaxamycins are reported.

Synthesis of an antigenic tetrasaccharide repeating unit of the O -polysaccharide of Salmonella enteritidis lipopolysaccharide has been accomplished. Those four monosaccharides were assembled stereoselectively by employing our recently developed cationic gold(I)-catalyzed glycosylation methodology involving various glycosyl N -1,1-dimethylpropargyl carbamate donors. The newly formed α-anomeric stereochemical configuration was controlled by the axial C2-OBz of the glycosyl donors via anchimeric assistance.

In 2017, the FDA authorized 5-aminolevulinic acid (5-ALA) for intraoperative optical imaging of suspected high-grade gliomas. This was the first authorized optical imaging agent for brain tumor surgery to enhance the visualization of malignant tissue. Herein we report the synthesis of a racemic and enantiopure fluorinated analog of 5-ALA, i.e., 3-fluoro-5-aminolevulinic acid (3F-5-ALA). We anticipate that these studies will provide the foundation for the future construction of a fluorine-18-labeled 5-ALA PET tracer to be used for functional and metabolic imaging of gliomas.

Polyunsaturated fatty acids and their metabolites have been reported in which their pathway has potential for the modulation of cancer cell growth. 13-( S )-HODE and 15-( S )-HETE, both of which are main metabolites of 15-LOXs, play an important role as endogenous ligands in biological systems. However, the modification of 13-( S )-HODE and 15-( S )-HETE in pharmaceutical applications has not been explored widely. Herein, we report the stereoselective syntheses of 13-( S )-HODE, 15-( S )-HETE, and its derivatives to enable the synthesis of bioactive fatty acid analogues.

Asymmetric reduction of 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-one (NEB-7) into 2-chloro-1-(6-fluorochroman-2-yl)ethan-1-ol (NEB-8) is the crucial step for synthesis of liposoluble β 1 receptor blocker nebivolol. Four efficient and stereoselective alcohol dehydrogenases were identified, enabling the stereoselective synthesis of all enantiomers of NEB-8 at a substrate loading of 137 g·L -1 with ee values of >99% and high space-time yields. This study provides novel biocatalysts for the efficient synthesis of nebivolol precursors and uncovers the molecular basis for enantioselectivity manipulation by parametrization of Prelog's rule.

The stereoselective synthesis of meso -diaminopimelic acid ( meso -DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its biological precursor, l,l-DAP, is described. The key step involved stereoselective reduction of a common enone-derived amino acid by substrate- or reagent-based control. Overman rearrangement of the resulting allylic alcohols, concurrent alkene hydrogenation and trichloroacetamide reduction, and subsequent ruthenium-catalyzed arene oxidation completed the synthesis of each stereoisomer. The synthetic utility of this approach was demonstrated with the efficient preparation of an l,l-DAP-derived dipeptide.

Baloxavir marboxil ( 1 ; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM ( 1 ) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM ( 1 ). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core (( R )- 14 ). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

A simple empirical method is described that allows the assignment of absolute configurations of natural products containing chiral vicinal bromochloro (VBC) units, including the bromochloro substituted isoprenyl units present in the structures of antiproliferative halomon ( 1a ) and its halogen-swapped isomer iso -halomon ( 1b ) from the red alga, Portieria hornemannii , and callophycols A ( 3 ) and B ( 4 ) from Callophycus serratus . The relative configurations of 3 and 4 , published in 2007, were incomplete: C-16 was left unassigned. It is now shown that the additivity of molar rotations, [ M ] D (herein, abbreviated [ M ])─a consequence of van't Hoff's principle of optical superposition─could be used to deconvolute rotatory contributions, designated as [ M X ] and [ M Y ] of the two remotely spaced chiral substructures within 3 and 4 using simple arithmetic. Input of proxy values, [ M Y 1 ] and [ M Y 2 ], for the two different VBC units in two equations for [ M X ] and application of a "conditional test" returns the same value for [ M X ] only when a proxy with the correct configuration is included. It is revealed that 3 and 4 have opposite configurations at the C-16 stereocenter: 16 S and 16 R , respectively. Two important implications lie in these findings: 3 and 4 appear to qualify as paired-regioisomers, coupled through a putative dyotropic rearrangement (DR), and the biosyntheses of other Callophycus secondary metabolites, now numbering over 50, are tightly controlled by stereoelectronic considerations including neighboring group interactions of the DR. It now appears, counter to earlier suggestions, that the chirality of Callophycus secondary metabolites, despite their high chemodiversity, are surprisingly highly conserved. Enantiofacial halogenation additions to the C═C double bonds of precursor alkenes appear to direct the formation of the remaining stereocenters at both the halogenated benzoate-decalin core and the distal VBC of 3 and 4 . A consistent hypothesis is proposed to account for macrolactonizations in other Callophycus natural products including bromophycolides A and B. The conditional test of molar rotations was applied in a different context to understand the chiroptical properties and trends observed in the highly iodinated meroditerpenes, iodocallophycols A-E, also from Callophycus sp., resulting in the revision of the configuration of callophycol E from (10 R ,14 R ) to (10 S ,14 S ).

Darunavir is a potent HIV protease inhibitor that has been established as an effective tool in the fight against the progression of HIV/AIDS in the global community. The successful application of this drug has spurred the development of derivatives wherein strategic regions (e.g., P1, P1', P2, and P2') of the darunavir framework have been structurally modified. An alternate route for the synthesis of darunavir and three related P1 and P1' derivatives has been developed. This synthetic pathway involves the use of a Crimmins titanium tetrachloride-mediated oxazolidine-2-thione-guided asymmetric glycolate aldol addition reaction. The resultant aldol adduct introduces the P1 fragment of darunavir via an aldehyde. Transamidation with a selected amine (isobutylamine or 2-ethyl-1-butylamine) to cleave the auxiliary yields an amide wherein the P1' component is introduced. From this stage, the amide is reduced to the corresponding β-amino alcohol and the substrate is then bis-nosylated to introduce the requisite p -nitrobenzenesulfonamide component and activate the secondary alcohol for nucleophilic substitution. Treatment with sodium azide yielded the desired azides, and the deprotection of the p -methoxyphenoxy group is achieved with the use of ceric ammonium nitrate. Finally, hydrogenation to reduce both the aniline and azide functionalities with concurrent acylation yields darunavir and its derivatives.

β-l-5-(( E )-2-Bromovinyl)-1-((2 S ,4 S )-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17 ) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU ( 17 ) has demonstrated excellent anti -VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24 ) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP ( 24 ), in vivo , effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP ( 24 ) is needed. In this article, an efficient approach for the synthesis of l-BHDU ( 17 ) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU ( 17 ) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24 ). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.

Cyclolithistide A is a peptide lactone isolated from marine lithistid sponges. Its entire structure, including absolute configurations, has been reported except the relative and absolute configurations of its characteristic residue, 4-chloroisoleucine (4-CIle). We synthesized four isomers of 4-CIle from furfural-derived N -Boc imine and propionaldehyde. Analysis of the acid hydrolysate of cyclolithistide A and the synthetic samples of 4-CIle after derivatization with l- and d-FDAA permitted us to propose the absolute configuration of the 4-chloroisoleucine residue in cyclolithistide A as 2 S ,3 R ,4 R .

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective β- O -glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.

S -Glycosides are more resistant to enzymatic and chemical hydrolysis and exhibit higher metabolic stability than common O -glycosides, demonstrating their widespread application in biological research and drug development. In particular, β- S -glycosides are used as antirheumatic, anticancer, and antidiabetic drugs in clinical practice. However, the stereoselective synthesis of β- S -glycosides is still highly challenging. Herein, we report an effective β- S -glycosylation using 3- O -trichloroacetimidoyl glycal and thiols under mild conditions. The C3-imidate is designed to guide Pd to form a complex with glucal from the upper face, followed by Pd-S (thiols) coordination to realize β-stereoselectivity. This method demonstrates excellent compatibility with a broad scope of various thiol acceptors and glycal donors with yields up to 87% and a β/α ratio of up to 20:1. The present β- S -glycosylation strategy is used for late-stage functionalization of drugs/natural products such as estrone, zingerone, and thymol. Overall, this novel and simple operation approach provides a general and practical strategy for the construction of β-thioglycosides, which holds high potential in drug discovery and development.

The short and first total synthesis of (+)-colletotryptins B-D, ent -colletotryptin A, and diastereomer of mucronatin B, which are a group of natural 3-(indol-2-yl)-3-(indol-3-yl)-1,2-propanediol (IIPDO) analogues containing two stereogenic centers at the C8' and C9' positions, isolated from endophytic fungus Colletotrichum sp. SC1355 and Tetrapterys mucronata , respectively, has been successfully accomplished in two and three steps with overall yields ranging from 28 to 54%. Key features of this synthesis include an innovative Bi(OTf) 3 -catalyzed stereoselective transindolylation of ( S )-3,3'-di(1 H -indol-3-yl)propane-1,2-diol. The operational simplicity, environmentally friendly catalyst, and broad functional group tolerance of this modular strategy render it suitable for adoption in both academic and industrial settings.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.

Activated acyl species have proven versatile in the esterification of 2'-OH groups in RNA, enabling structure mapping, caging, profiling, and labeling of the biopolymer. Nearly all reagents developed for this reaction have been achiral; however, a recent study reported that simple chiral amino acid acylimidazole derivatives could yield diastereoselective reactions at RNA 2'-OH in water, enabling up to 4:1 selectivity in screening. Here, we investigated the effect of steric bulk on the stereoselectivity of RNA reaction and on the stability of adducts with a library of 36 chiral acylimidazole scaffolds with increasing steric demand. The results document the highest stereoselectivity yet achieved in RNA acylation reactions, with as high as >99:1 diastereoselectivity at >70% conversion. Also notably, the bulky adducts were found to have markedly improved stability on RNA.

Herein, the execution of synthetic strategies solving scalability issues observed in the original route is reported, increasing the total yield by 50% compared to the previously disclosed synthesis. A notable restructuring of the route's initial steps to reach a common allylic alcohol intermediate employs a highly stereoselective epoxidation method and avoids superfluous protecting group manipulations while limiting dependence on kinetic resolution in establishing stereochemistry for four of the six chiral centers in (+)-desmethylxestospongin B. Different protecting group strategies to avoid problems with their subsequent removal were considered and enacted; to this end, material was retained as byproducts were suppressed. While the lactam semireduction under Birch conditions requires further investigation, the updated synthesis of (+)-desmethylxestospongin B reported here made it more scalable, affording 0.37 g of this natural product for continued biological studies.

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a , respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

The enantioselective synthesis of chiral diarylmethanols is highly desirable in synthetic chemistry and the pharmaceutical industry, but it remains challenging, especially in terms of green and sustainable production. Herein, a resin-immobilized palladium acetate catalyst was fabricated with high activity, stability, and reusability in Suzuki cross-coupling reaction of acyl halides with boronic acids, and the coimmobilization of alcohol dehydrogenase and glucose dehydrogenase on resin supports was also conducted for asymmetric bioreduction of diaryl ketones. Experimental results revealed that the physicochemical properties of the resins and the immobilization modes played important roles in affecting their catalytic performances. These two catalysts enabled the construction of a chemoenzymatic cascade for the enantioselective synthesis of a series of chiral diarylmethanols in high yields (83-90%) and enantioselectivities (87-98% ee). In addition, the asymmetric synthesis of the antihistaminic and anticholinergic drugs ( S )-neobenodine and ( S )-carbinoxamine was also achieved from the chiral diarylmethanol precursors, demonstrating the synthetic utility of the chemoenzymatic cascade.

Although the construction of peptides with well-defined three-dimensional structures and predictable functions, including biological activity, using conformationally constrained β-amino acids has been shown to be a very successful strategy, their broad application is limited by access to the appropriate building blocks. In particular, trans - and cis -stereoisomers of 2-aminocyclopentanecarboxylic acid (ACPC) are of high interest. The scalable synthesis of all four stereoisomers of Fmoc derivatives of ACPC is presented with NMR-based analysis methods for their enantiomeric purity.

A streamlined and efficient approach to the key epoxide intermediate for the asymmetric synthesis of triazole antifungal agents is presented. This synthesis highlights a P(NMe 2 ) 3 -mediated nonylidic olefination of α-keto ester, ensuring the exclusive formation of the requisite ( Z )-alkene, followed by a highly enantioselective Jacobsen epoxidation to establish the two vicinal stereocenters in a single step. The versatility of this strategy is exemplified through the efficient synthesis of efinaconazole and ravuconazole.

CIDD-0072424 is a novel small molecule developed in silico with remarkable activity for the inhibition of protein kinase C (PKC)-epsilon to treat alcohol use disorder. We developed a concise synthesis of ( S )- 2 that is highly enantioselective, scalable, and amenable for 3-point structure-activity relationship (SAR) studies for compound optimization. The highly enantioselective nitro-Mannich reaction was achieved through a dual-reagent catalysis system. The overall utility and the efficiency of the enantioselective route provided a scalable synthesis of both PKCε inhibitors 1 and 2 .

A highly stereoselective total synthesis of potent multidrug-resistant reverser dysoxylactum A has been accomplished in the longest linear sequences of 20 steps with an overall 10.2% yield. The key steps of this synthesis included Brown's crotylation, Evans alkylation, the Carreira protocol to generate the stereogenic center, and Yamaguchi macrolactonization.

We describe the gram-scale synthesis of (-)-(1 R ,2 S ,3 R ,4 R ,5 S ,6 S )-1,3-di(diamino)-1,3-diazido-2,5,6-tri- O -benzylstreptamine from streptomycin by (i) hydrolysis of the two streptomycin guanidine residues, (ii) reprotection of the amines as azides, (iii) protection of all alcohols as benzyl ethers, and (iv) glycosidic bond cleavage with HCl in methanol. Protocols for regioselective monodebenzylation and regioselective reduction of a single azide in the product are also described, providing four optically pure building blocks for exploitation in novel aminoglycoside synthesis.

A catalytic enantioselective synthesis of bicalutamide derivatives with promising potentials in prostate cancer treatment has been disclosed. The key intermediates, α-hydroxy-β-keto esters, were efficiently constructed through cinchoninium-mediated asymmetric oxohydroxylation of easily accessible alkenes with potassium permanganate. Good yields and high levels of asymmetric induction are achieved. This method provides a new synthetic route to bicalutamide analogues with high structural diversity, which will beneficially support subsequent structure-activity relationship studies and boost prostate cancer drug development.

Enzyme-catalyzed dynamic kinetic resolution was applied to the one-pot regio- and enantioselective synthesis of 2,5-disubstituted tetrazole hemiaminal esters, among which 72% of the products were obtained in excellent enantiopurities (99% ee s). Tunable stereoselectivity was achieved by using different types of enzymes during the synthesis of a key intermediate for a clinic drug candidate. Successful preparation of tetrazole ester prodrugs and high catalyst recyclability further demonstrated the potential practical application of this protocol.

An exemplary blend of chiral pool with chiral catalysis is exhibited in an eight-step (longest) convergent asymmetric total synthesis of mycalol, which is a promising anticancer natural lipid from a marine source. The polyhydroxy lipid is constructed by using four blocks, and two of which are derived from the chiral pool (d-mannitol and d-gluconolactone) and the other two by chiral catalysis (Sharpless epoxidation and Keck allylation). Alkylation and metathesis were used to knit the blocks in an excellent display of a modular convergent eight-step synthesis. The modular excess will enable rapid analogue generation as revealed by the convenient synthesis of 4- epi -mycalol similarly in an eight-step sequence.

The first synthesis of ustusal A as well as expeditious access to (-)-albrassitriol is described as featuring a singlet oxygen [4 + 2] cycloaddition, achieving the desired stereoselectivity for the 1,4- cis -hydroxyl groups. Transformation of (+)-sclareolide to III followed by a key Horner-Wadsworth-Emmons (HWE) reaction and stereospecific allylic oxidation facilitated the first synthesis of elegansin D. The biological evaluation of these natural products together with seven elegansin D analogues was performed, among which several elegansin D analogues exhibited potential anticancer activity against liver cancer HepG2 cells (IC 50 = 11.99-25.58 μM) with low cytotoxicity on normal liver HL7702 cells (IC 50 > 100 μM).

Enantioselective synthesis of nabscessin C ( 1 ), an aminocyclitol amide with antimicrobial activity, is reported. Starting from myo -inositol, (+)-nabscessin C was synthesized in 12 isolation steps. Desymmetrization of 2-deoxygenated 4,6-dibenzylinositol was achieved using lipase from porcine pancreas (PPL), and the stereochemistry was established by X-ray crystallography. This method has the potential for synthesizing other cyclitol-derived compounds.

During studies of atroposelective, peptide-catalyzed N -oxidations of pyridines, we observed lower-than-expected barriers to atropisomerization for these stereodynamic processes under the reaction conditions. Mechanistic studies indicate a hydrogen bond-assisted racemization mechanism intrinsic to both the starting materials and products. We also identified a protonation-dependent barrier to rotation that operates for the starting materials alone. Nonetheless, several substrates were amenable to atroposelective N -oxidations via kinetic resolution, yielding k rel values of up to 12.6 and the isolation of one N -oxide with >99:1 er after recrystallization.

Borate esters have been applied widely as coupling partners in organic synthesis. However, the direct utilization of borate acceptors in O -glycosylation with glycal donors remains underexplored. Herein, we describe a novel O -glycosylation resulting in the formation of 2,3-unsaturated O -glycosides and 2-deoxy O -glycosides mediated by palladium and copper catalysis, respectively. This O -glycosylation method tolerated a broad scope of trialkyl/triaryl borates and various glycals with exclusive stereoselectivities in high yields. All the desired aliphatic/aromatic O -glycosides and 2-deoxy O -glycosides were generated successfully, without the hemiacetal byproducts and O→C rearrangement because of the nature of borate esters. The utility of this strategy was demonstrated by functionalizing the 2,3-unsaturated glycoside products to form saturated β- O -glycosides, 2,3-deoxy O -glycosides, and 2,3-epoxy O -glycosides.

2,2-Disubstituted-3-hydroxycyclopentanones are important chiral intermediates for natural products and pharmaceuticals. Through semirational engineering of a thermostable carbonyl reductase CBCR from Cupriavidus sp. BIS7, a mutant L91C/F93I was obtained. Mutant L91C/F93I showed 4- to 36-fold enhanced activities toward 2-methyl-2-benzyl-1,3-cyclopentanedione and its analogues, affording the (2 R ,3 R )-stereoisomers with >99% ee and >99% de. Enzyme-substrate docking studies were performed to reveal the molecular basis for the activity and stereoselectivity improvements.

5'- O -(2-Methoxyisopropyl) (MIP)-protected 2'-deoxynucleosides as chiral P(V)-building blocks, based on the limonene-derived oxathiaphospholane sulfide, were synthesized and used for the assembly of di-, tri-, and tetranucleotide phosphorothioates on a tetrapodal pentaerythritol-derived soluble support. The synthesis cycle consisted of two reactions and two precipitations: (1) the coupling under basic conditions, followed by neutralization and precipitation and (2) an acid catalyzed 5'- O -deacetalization, followed by neutralization and precipitation. The simple P(V) chemistry together with the facile 5'- O -MIP deprotection proved efficient in the liquid phase oligonucleotide synthesis (LPOS). Ammonolysis released nearly homogeneous Rp or Sp phosphorothioate diastereomers in ca. 80% yield/synthesis cycle.

Nitro-substituted donor-acceptor cyclopropanes react with salicylaldehydes in the presence of cesium carbonate in water to give new chromane derivatives. The reaction takes place through in situ formation of allene intermediates from the cyclopropanes and subsequent Michael-initiated ring closure of the intermediates with salicylaldehydes.

Herein we report a catalytic asymmetric inverse-electron-demand Diels-Alder reaction between alkylidene pyrazolones and allyl ketones. Allyl ketone gets activated by a bifunctional thiourea catalyst and acts as a dienolate in this reaction. The trisubstituted tetrahydropyrano[2,3- c ]pyrazoles were obtained in moderate to good yields with high diastereo- and enantioselectivities. Few applications, including a decarbonylation reaction, have been demonstrated.

Recently, we synthesized the proposed structure of the fungal glycolipid fusaroside and suggested corrections in its structure with respect to the positions of the double bonds in the lipid portion. Herein, we report the first total synthesis of the proposed revised structure of fusaroside and thereby confirm its structure. The synthesis involved Julia-Kocienski olefination for the construction of fatty acid and its coupling with trehalose at the O4 position followed by late-stage gem-dimethylation as key steps.

Cyclobutane scaffolds are incorporated in several valuable natural and bioactive products. However, non-photochemical ways to synthesize cyclobutanes have scarcely been investigated. Herein, based on the principles of the electrosynthesis technique, we introduce a novel electrochemical approach for attaining cyclobutanes by a simple [2 + 2] cycloaddition of two electron-deficient olefins in the absence of photocatalysts or metal catalysts. This electrochemical strategy provides a suitable condition for synthesizing tetrasubstituted cyclobutanes with a variety of functional groups in good to excellent efficiency, compatible with gram-scale synthesis. In contrast to previous challenging methods, this approach strongly focuses on the convenient accessibility of the reaction instruments and starting materials for preparing cyclobutanes. Readily accessible and inexpensive electrode materials are firm evidence to prove the simplicity of this reaction. In addition, mechanistic insight into the reaction is obtained by investigation of the CV spectra of the reactants. Also, the structure of a product is identified by X-ray crystallography.

A Ni-catalyzed enantioselective intramolecular Mizoroki-Heck reaction has been developed to transform symmetrical 1,4-cyclohexadienes with attached aryl halides into phenanthridinone analogues containing quaternary stereocenters. Herein, we report important advances in reaction optimization enabling control of unwanted proto-dehalogenation and alkene reduction side products. Moreover, this approach provides direct access to six-membered ring heterocyclic systems bearing all-carbon quaternary stereocenters, which have been much more challenging to form enantioselectively with nickel-catalyzed Heck reactions. A wide range of substrates were demonstrated to work in good to excellent yields. Good enantioselectivity was demonstrated using a new synthesized chiral i Quinox-type bidentate ligand ( L27 ). The sustainability, low price of nickel catalysts, and significantly faster reaction rate (1 h) versus that of a recently reported palladium-catalyzed reaction (20 h) make this process an attractive alternative.