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Halogenated phenazine meroterpenoids are a structurally unusual family of marine actinobacterial natural products that exhibit antibiotic, antibiofilm, and cytotoxic bioactivities. Despite a lack of established phenazine halogenation biochemistry, genomic analysis of Streptomyces sp. CNZ-289, a prolific lavanducyanin and C2-halogenated derivative producer, suggested the involvement of vanadium-dependent haloperoxidases. We subsequently discovered lavanducyanin halogenase (LvcH), characterized it in vitro as a regioselective vanadium-dependent chloroperoxidase, and applied it in late-stage chemoenzymatic synthesis.

Enantioselective cyclopropanation of α-carbonyl sulfoxonium ylides (SY) has so far been limited to addition/ring closure reactions on electron-poor olefins. Herein, we report the iridium-catalyzed intramolecular cyclopropanation of SY in the presence of a chiral diene in up to 96% yield and 98% enantioselectivity. Moreover, density functional theory calculations suggest that the re face of the olefin preferably attacks an iridium carbene intermediate in an asynchronous concerted step that is independent of the geometry of the olefin.

Efficient access to chiral cyclopentadienyl esters from readily accessible chiral enynyl ester substrates is developed. Typically high levels of chirality transfer realized in this homogeneous gold catalysis are attributed to the intermediacy of a chiral bent allene gold complex. Cyclopentadienyl esters can be prepared in good yields and with excellent enantiomeric excesses. The synthetic utilities of the chiral cyclopentadienyl esters are demonstrated by the Diels-Alder reactions, fluorination, alkylation, and epoxidation without any notable erosion of enantiopurity.

An anionic oxy-Cope/transannular Michael addition cascade converts a spirocyclic architecture-readily available by Diels-Alder cycloaddition-into the hydrophenalene carbon skeleton of the pseudopterosin aglycones. Oxidation of the resulting cyclohexenone ring to the phenol that is characteristic of the targets completes a short formal synthesis.

Pyonitrins A-D are recently isolated natural products from the insect-associated Pseudomonas protegens strain, which were isolated from complex fractions that exhibited antifungal activity via an in vivo murine candidiasis assay. Genomic studies of Pseudomonas protegens suggested that pyonitrins A-D are formed via a spontaneous nonenzymatic reaction between biosynthetic intermediates of two well-known natural products pyochelin and pyrrolnitrin. Herein we have accomplished the first biomimetic total synthesis of pyonitrins A-D in three steps and studied the nonenzymatic formation of the pyonitrins using 15N NMR spectroscopy.

The formation of fused pyrazoles via intramolecular 1,3-dipolar cycloadditions of diazo intermediates with pendant alkynes is described. A subsequent thermal [1s, 5s] sigmatropic shift of these pyrazole systems resulted in a ring contraction, forming spirocyclic pyrazoles. The limitations of this rearrangement were explored by changing the substituents on the nonmigrating aromatic ring and by using substrates lacking an aromatic linkage to the propargyl group.

A novel phosphine-catalyzed intermolecular cyclization between 2-sulfonamidobenzaldehyes and ynones is reported. This methodology serves as a conduit for the construction of benzo[ b]azepin-3-ones in good to excellent yields under mild conditions. The resulting 2-benzylidene moieties are formed exclusively in the E-configuration. Mechanistically, this unusual annulation occurs through a phosphine-catalyzed α-umpolung addition, followed by an aldol reaction. One of the benzo[ b]azepin-3-one products was converted to the core structure of 3-amino-[ a]benzazepin-2-one-1-alkanoic acids, many of which function as angiotensin-converting enzyme inhibitors.

The Mannich reaction has been used for decades to prepare many pharmaceutically important molecules. Here, using a "double-Mannich-β-elimination" synthetic sequence, we report the synthesis and the characterization details of a novel class of β-amino diaryldienones with prominent antiprostate cancer activity. Through these studies, we correct an erroneous structure in the current literature, present a discussion of the stereochemical outcome of a new reaction, and probe the mechanism(s) of byproduct formation through isotopic studies.

Spliceostatin A is a potent inhibitor of spliceosomes and exhibits excellent anticancer activity against multiple human cancer cell lines. We describe here the design and synthesis of a stable cyclopropane derivative of spliceostatin A. The synthesis involved a cross-metathesis or a Suzuki cross-coupling reaction as the key step. The functionalized epoxy alcohol ring was constructed from commercially available optically active tri- O-acetyl-d-glucal. The biological properties of the cyclopropyl derivative revealed that it is active in human cells and inhibits splicing in vitro comparable to spliceostatin A.

P-Chiral [2.2.1] bicyclic phosphines (HypPhos catalysts) have been applied to reactions between α-alkylallenoates and imines, producing guvacine derivatives. These HypPhos catalysts were assembled from trans-4-hydroxyproline, with the modular nature of the synthesis allowing variations of the exocyclic P and N substituents. Among them, exo-( p-anisyl)-HypPhos was most efficacious for [4 + 2] annulations between ethyl α-methylallenoate and imines. Through this method, ( R)-aplexone was identified as being responsible for the decrease in the cellular levels of cholesterol.

A DP4 protocol has been successfully utilized to establish the true structure of the natural product cyclocinamide A, a flexible cyclic peptide with four isolated stereocenters. Benchmarking the necessary level of theory required to successfully predict the NMR spectra of three previously synthesized isomers of cyclocinamide A led to the prediction of the natural stereochemistry as 4 S, 7 R, 11 R, 14 S, which has been confirmed by total synthesis.

The synthesis of radiolabeled [25- 14 C]-siamenoside I following a synthetic route developed using unlabeled materials is disclosed. The synthesis features an early stage labeling of the mogrol's C25 via an oxidative cleavage-reconstruction strategy and regioselective glycosylations directed by protecting group manipulations. This route provided access to adequate amounts of [25- 14 C]-siamenoside I for in vivo ADME and PK studies.

Synthesis of complex, multiring, spirocyclic, 1,3-dicarbonyl fused, and highly functionalized 5-phenyl-1-azabicyclo[3.1.0]hexanes (ABCH) has been achieved by an intermolecular reaction of 2-(2'-ketoalkyl)-1,3-indandiones or α,γ-diketo esters with (1-azidovinyl)benzenes under transition metal-free conditions. The reaction proceeds in a highly diastereoselective manner with a wide range of functional groups and provides moderate to good yields. Additionally, we have studied the preliminary biological activities of a few synthetic compounds against HeLa and triple-negative breast cancer (TNBC) cell lines.

We present an efficient synthetic pathway for kasugamycin, an aminoglycoside antibiotic, utilizing naturally derived carbohydrates as starting materials. This synthesis effectively addresses stereochemical complexities by employing the selective reduction of d-fucal, which generates a crucial 3-deoxyglycal intermediate. This intermediate facilitates the introduction of amino groups at the C-2 and C-4 positions, which is essential for the synthesis of kasugamine. Subsequent glycosylation with glycosyl 1- O - m -chlorobenzoate ( m CBz) donors yields a disaccharide intermediate, which is further transformed to produce kasugamycin. This streamlined approach provides a practical and effective route for the synthesis of kasugamycin and related deoxy amino sugar-containing antibiotics.

Neaumycin B is a complex polyketide that shows phenomenal cytotoxicity against U87 glioblastoma cells. The singly anomeric spiroketal core is a notable subunit in the natural product's structure. We report a rapid and convergent approach to the spiroketal group, resulting in the formation of two isomeric singly anomeric spiroketals. We describe the origin of this rarely described outcome in spirocycle formation and subsequently propose a correction to a stereocenter in the natural product.

Utilizing enzymes as biocatalysts, an alternative strategy has been developed for the highly enantioselective synthesis of chiral 2,3-dihydrobenzofuran (2,3-DHB) esters via the dynamic kinetic resolution of 2,3-dihydro-3-benzofuranols, which are generated from an intramolecular Aldol reaction. This protocol provides easy access to a series of 2,3-DHB ester derivatives, prodrugs, and allows for functional group transformations. Biological evaluation also indicates that some of the products exhibit potent anti-inflammatory activity.

The general synthesis of chiral unnatural aromatic amino acids has rarely been reported. We herein describe a visible light-promoted copper-catalyzed enantioselective C(sp 3 )-H benzylation of glycine derivatives. The method demonstrated compatibility in coupling various N -hydroxyphthalimide (NHP) esters derived from aromatic acids with glycine derivatives, providing a general protocol for synthesizing analogues of phenylalanine, tryptophan, and tyrosine. This protocol features mild conditions, high enantioselectivity, excellent functional group tolerance, and important impacts on the development of peptide drugs.

(+)-Brevianamides A ( 1a ) and B ( 1b ) are distinguished by their unique bicyclo[2.2.2]diazaoctane structure and have captured the interest of synthetic chemists due to their fascinating array of biological activities. The biosynthetic proposal of these classes of alkaloids led to the discovery of a number of interesting strategies. We present a biomimetic synthesis of these alkaloids starting from naturally occurring 4-hydroxy-l-proline and L-tryptophan. Gratifyingly, we emulate an alternative biosynthetic process through a unique elimination-isomerization sequence triggered by a dual-base system to generate the key aza -diene required for the Diels-Alder reaction to craft the bicyclo[2.2.2]diazaoctane structure.

Genome mining and gene deletion experiments in Penicillium crustosum proved the involvement of the PKS-NRPS PemA and the trans -enoyl reductase PemB in the formation of three enantiomeric clavatol-containing tetramate pairs. Overexpression of a transcription factor significantly improved the product yields. Feeding experiments provided evidence for their formation via 1,4-Michael addition of hydroxyclavatol to two tetramates from the Pem pathway. This study provides another example of the involvement of reactive intermediates in multiple biosynthetic pathways.

A Ph 3 PO-modulated β-selective Kdo glycosidation approach is developed for the stereoselective synthesis of β-Kdo glycosides. With the readily available per- O -acetylated Kdo ynenoate as the donor, the glycosylation with a series of alcohols in the presence of Ph 3 PAuOTf and Ph 3 PO in toluene at low temperatures afforded the desired Kdo glycosides with good to excellent β-selectivities. Furthermore, the Ph 3 PO-modulated approach was effectively applied to the synthesis of β-(2→4)- and β-(2→8)-linked Kdo-Kdo disaccharides for further biological studies.

Following the satisfactory catalytic performance of cobalt in the C -glycosylation of glycals, further study of cobalt's application values was performed under mild conditions, leading to a range of highly α-stereoselective 2,3-unsaturated O- , S- , and N- glycosides. The synthetic potential of the developed protocol was underscored by the late-stage functionalization of pharmaceutically relevant molecules including the canagliflozin derivative (a potential candidate for treating type 2 diabetes and alleviating pathological aging). Furthermore, control experiments were conducted to elucidate a reasonable mechanism and rule out the pathway involving the configuration conversion between α- and β- anomers.

Thuggacin A ( 1 ) is a 17-membered-ring-polyketide antibiotic compound with excellent antituberculosis activity. The total synthesis of thuggacin A has not yet been reported so far. Herein, we disclose our efforts toward the convergent total synthesis of thuggacin A. The key synthetic features include our own one-pot cascade thiazole formation, Evans syn -aldol, Mukaiyama asymmetric aldol reaction, organosilicon-promoted selective alkyne reduction, Shiina macrolactonization, and a nucleophilic ring-opening of epoxide with alkyne to assemble the main framework of thuggacin A. The enantioselective synthesis of trimethylsilyl ethoxymethyl (SEM) derived thuggacin A analogue 2 was achieved in 18 longest linear steps with 2.0% overall yield, and the bioassay of 2 exhibited moderate antituberculosis activity with minimum inhibitory concentration (MIC) of 320 μg/mL.

We report the synthesis of the antimicrobial cyclodepsipeptides marformycin A ( 1 ) and marformycin D ( 2 ) using a solid-phase approach. A scalable solution-phase synthesis of the γ-hydroxypiperazic acid subunit in 2 , starting from cis -hydroxyproline, is also described. Structural analysis of 1 and its Leu- epi congener demonstrates conformational differences that may underlie their divergent antimicrobial activities. The described approach enables further development of conformation-activity relationships within this class of depsipeptide natural products.

Herein, we have explored a one-pot bis-triflation and regioselective displacement protocol with d-fucose 2,4-diol to access various rare 6-deoxy amino d-sugars. This strategy enabled the first total synthesis of the trisaccharide unit of Pseudomonas stutzeri OX1 strain containing d-perosamine and d-tomosamine. Installation of a 1,2- cis linkage and late-stage N -formylation are the key challenges in the total synthesis, which was accomplished via the longest linear sequence of 21 steps with 1.2% overall yield.

The first total synthesis of the heptapeptide Cyclomarin A (CymA) was achieved via new routes to chiral amino acid building blocks (highlighted) and solid-phase peptide synthesis. A structurally misassigned epimer of CymA (CymA'), Cyclomarin C, and Metamarin were also synthesized. Affirmation of the syntheses was corroborated by observations that the synthetic molecules have antimicrobial activities mirroring those of the natural products. Interestingly, CymA' is more potent than CymA.

A chemoenzymatic synthesis access to resibufogenin and bufalin was developed in seven steps without protecting groups. Starting with androstenedione (AD), an α-OH was introduced directly at C14 by hydroxylase P-450 lun , which was further used as the directing group for hydrogenation to fully control the C17 configuration in the β-orientation after Suzuki cross-coupling. Dehydration of 14α-OH followed by an epoxidation delivered resibufogenin. Simultaneously, bufalin was also obtained via a challenging anaerobic Mukaiyama hydration.

Herein, we describe a chemoenzymatic and diversity-oriented approach for the first syntheses of octasaccharide repeating units of the capsular polysaccharides of Haemophilus parasuis serovar 15 and serovar 5. The synthetic method features efficient enzymatic assembly of sialyl galactose or N -acetyl-galactosamine building blocks, highly stereoselective chemical construction of α-type H -phosphonate, and the β-stereospecific 1,3-glycosylation reaction of a rare sugar donor.

An enantioselective total synthesis of spliceostatin G has been accomplished. The synthesis involved a Suzuki cross-coupling reaction as a key step. The functionalized tetrahydropyran ring was constructed from commercially available optically active tri-O-acetyl-d-glucal. Other key reactions include a highly stereoselective Claisen rearrangement, a Cu(I)-mediated 1,4 addition of MeLi to install the C8 methyl group, and a reductive amination to incorporate the C10 amine functionality of spliceostatin G. Biological evaluation of synthetic spliceostatin G and its methyl ester revealed that it does not inhibit splicing in vitro.

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration.

A method for determining the absolute configuration of β-chiral primary alcohols has been developed. Enantioenriched alcohols were acylated in the presence of either enantiomer of the enantioselective acylation catalyst HBTM, and the faster reaction was determined by measuring product conversion using 1H NMR spectroscopic analysis. An empirical mnemonic was developed that correlates the absolute configuration of the alcohol to the faster reacting catalyst. Successful substrates for this method include primary alcohols that bear a "directing group" on the stereogenic center; directing groups include arenes, heteroarenes, enones, and halides.

Transition-metal-catalyzed asymmetric α-arylation of carbonyl compounds is a widely studied method for C-C bond formation. Recently, the α-arylation of α-fluoro ketones has been reported, including enantioselective α-arylation of α-fluoro ketones. However, the asymmetric α-arylation of α-fluoro carbonyl compounds in the carboxylic acid oxidation state has not been reported. We report the enantioselective α-arylation of α-fluorooxindoles with aryl triflates. The reaction occurs in high yield and with high enantioselectivity when catalyzed by a Pd-Segphos complex. This general class of product serves as an enantioenriched, nonenolizable version of α-aryl oxindoles.

The first syntheses of the Alpinia officinarum natural products alpinidinoid C and officinine B are reported. These unusual dimeric diarylheptanoids were accessed from a 3-substituted pyridine intermediate via a blue-light-mediated, triple-Minisci-type alkylation. Very few reports utilize N -(acyloxy)phthalimides (NAPs) in the construction of natural products, and the syntheses reported herein highlight the power of this methodology toward the orthogonal construction of highly substituted arenes.

We report a general approach for efficient deuteration of the metabolically labile α-C-H bonds of widespread amides and amines. Temporarily masking the secondary amine group as a carbamate allows an unprecedented photoredox hydrogen atom transfer-promoted α-carbamyl radical formation for efficient H/D exchange with D 2 O. The mild protocol delivers structurally diverse α-deuterated secondary amines including "privileged" piperidine and piperazine structures highly regioselectively with excellent levels of deuterium incorporation (≤100%). Furthermore, we successfully implemented the strategy for α-deuteration of amides, lactams, and ureas with high regioselectivity and high levels of D incorporation. Finally, the observed efficient deuteration of secondary alcohol moieties in late-stage modification of complex amine-containing pharmaceuticals allows for the development of a viable method for efficient α-deuteration of the important functionality.

Acovenoside A ( 1 ), a cardiac glycoside featuring a unique l-acovenose at C-3 and a 1β,3β,14β-trihydroxy aglycone (namely, acovenosigenin A), shows promising antiproliferative activities. Herein, we report the synthesis of acovenoside A ( 1 ) together with a panel of its congeners. The synthesis features the stereoselective introduction of the 1β,14β-OH and C17-butenolide moieties starting from androstenedione ( 7 ) and gold(I)-catalyzed glycosylation with superarmed glycosyl ortho -alkynylbenzoates as donors.

Organoborons have recently received much attention, while a biocatalytic platform for the synthesis of chiral organoborons is limited only to Rma cytochrome c . In this study, we exploited the other heme protein, neuroglobin (Ngb), and engineered a quadruple mutant, A15C/H64G/V68F/F28M Ngb, by redesigning the heme active site using the structural information on A15C Ngb and molecular docking studies. The enzyme was shown to be efficient in catalyzing carbene transfer B-H insertion reactions between pyridine/quinoline boranes and benzyl 2-diazopropanoates and their derivatives (29 examples). The designed cavity in the heme distal site favors the binding of large volume substrates such as those containing a quinoline, naphthyl, or biphenyl group. As further determined by the X-ray crystallography of 6c , the chiral products are in the R -configuration, with up to 98:2 e.r. Furthermore, both the whole cell and cell lysate containing the enzyme are reactive toward the B-H insertion reactions. This study presents a convenient biocatalytic platform that may be generally applicable for the synthesis of functional chiral organoborons.

We report the stereoselective total synthesis of rhodocoranes I and J in 10 steps and 16.4% overall yield from ( S )-limonene. The synthesis was accomplished through the convergent assembly of a highly substituted chiral cyclopentanone and a lithiated furanyl silyl ketene acetal. The requisite cyclopentanone framework was strategically constructed from the chiral pool, ( S )-limonene, through a sequence of steps that included a hydroboration/oxidation, ozonolysis, aldol condensation, reduction, and palladium-catalyzed diastereoselective allylic transposition. This study provides a general approach to the synthesis of the rhodocorane family, known for their antibacterial, antifungal, and cytotoxic properties.

The first synthesis of chlorine-containing hemiketals, rumphellatins A-C ( 1 - 3 ), previously inaccessible by means of total synthesis, was achieved starting from commercially available (-)-β-caryophyllene oxide ( 7 ). Structures of rumphellatins A ( 1 ) and C ( 3 ) were revised, while structures of rumphellatin B ( 2 ) and intermediate rumphellolide C ( 19 ) were confirmed. The study expands availability of exotic norsesquiterpenoids for profiling their biological activity as well as facilitates the elucidation of biosynthetic pathways of their formation.

Less steric ketones exhibited low stereoselectivity toward M5 due to their difficulty in restricting the free rotation of the imine intermediate. An engineered enantio-complementary imine reductase from M5 was obtained with catalytic activity. We identified four key residues that play essential roles in controlling stereoselectivity. Two mutants, I149Y-W234L (up to 99% S ee ) and L200M-F260M (up to 99% R ee ), were achieved, showing excellent stereoselectivity toward the tested substrates, offering valuable biocatalysts for synthesizing alkylated amphetamines.

This study presents a total synthesis and revision of the stereochemical configuration of a potent antimalarial lead compound 2 possessing a benzo-pyranone framework, which was derived from the (+)-monocerin natural product of marine fungi, Exserohilum sp . Chiral hypervalent iodine(III)-catalyzed oxylactonization and late-stage O -methylation were highlights of the synthesis, which enabled access to the library of all possible eight stereoisomers of 2 for further understanding of stereochemical structure activity relationships (S-SARs).

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

A peptide-catalyzed enantioselective oxidation of sulfides to yield pharmaceutically relevant chiral sulfoxides is reported. Experimental evidence suggesting that a hydrogen bond-donating moiety must be present in the substrate to achieve high levels of enantioinduction is supported by computational modeling of transition states. These models also indicate that dual points of contact between the peptidic catalyst and substrate are likely responsible for the formation of one desired sulfoxide in 94:6 er.

Lappaconitine, a diterpene alkaloid isolated from Aconitum sinomontanum Nakai, exhibits a wide range of biological activities, making it a promising candidate for the development of novel derivatives with therapeutic potential. In our research, we executed a two-step transformation via oxidative cleavage of lappaconitine's vicinal diol using the hypervalent iodine reagent PhI(OAc) 2 , followed by strong alkaline hydrolysis. This approach yielded four new unanticipated compounds, whose structures were identified by spectroscopic methods and/or X-ray crystallography. Thus, we proposed plausible reaction mechanisms for their formations and particularly investigated the remarkable diastereoselectivity for the formation of single stereoisomer 8 observed during the alkaline hydrolysis step. Among them, compound 8 (code name: QG3030 ) demonstrated both enhanced osteogenic differentiation of human mesenchymal stem cells and significant osteogenic effect in an ovariectomized rat model with no acute oral toxicity.

Asperalins represent a novel class of viridicatin natural products with potent inhibitory activities against fish pathogens. In this study, we elucidated the biosynthesis of asperalins in the Aspergillus oryzae NSAR1 heterologous host and identified the FAD-dependent monooxygenase AplB stereoselectively hydroxylates viridicatin to yield a unique 3 R ,4 S configuration. The monomodular NRPS AplJ catalyzes a rare intramolecular ester bond formation reaction using dihydroquinoline as a nucleophile. Subsequent modifications by cytochrome P450 AplF, chlorinase AplN, and prenyltransferase AplE tailor the anthranilic acid portion, leading to the formation of asperalins. Additionally, we explored the potential of AplB for the hydroxylation of viridicatin analogs, demonstrating its relaxed substrate specificity. This finding suggests that AplB could be developed as a biocatalyst for the synthesis of viridicatin derivatives.

Herein, we present a highly efficient method for constructing the intricate 5-5-6 fused ring system commonly found in the polycyclic furanobutenolide-derived cembranoid and norcembranoid natural product family with remarkable diastereoselectivity, utilizing an intramolecular Diels-Alder reaction as the cornerstone. Notably, employing a propargyl ether tether as the dienophile yields significant enhancements in the transformation process compared to its propargyl ester counterpart, as demonstrated in our previous total synthesis of havellockate. This advancement holds promising implications for future investigations, offering a streamlined pathway for rapidly assembling the tricyclic core characteristic of this diverse family of natural products.

Copper-catalyzed reactions of glycine ester arylimines and methacrylonitrile provide selective access to either the endo or exo pyrrolidine cycloadducts. DFT calculations have elucidated the origins of ligand-controlled diastereoselectivity.

The enantioselective silver-catalyzed propargylation of N-sulfonylketimines is described. This reaction proceeds in high yield and excellent enantiomeric ratio and is compatible with a wide variety of diaryl- and alkylketimines. Synthetic transformations of homopropargylic products via enyne ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions proceed with high stereochemical fidelity. Both allenyl and propargyl borolane reagents can be used to obtain homopropargylic products, a distribution most consistent with a mechanism involving transmetalation of the silver catalyst with the borolane reagent.

The first example of a general asymmetric nitrosocarbonyl hetero-ene reaction is described. The procedure uses a copper-catalyzed aerobic oxidation of a commercially available chiral nitrosocarbonyl precursor (EleNOr) and is operationally simple. The transformation is both high yielding and highly diastereoselective for a range of silyl enol ether derivatives. A variety of synthetically useful postfunctionalization reactions are presented along with a mechanistic rationale that can be used as a predictive model for future asymmetric reactions with nitrosocarbonyl intermediates.

Highly torquoselective electrocyclizations of chiral 1-azatrienes are described. These 1-azatrienes contain an allylic stereocenter that is substituted with a silyl group and are derived in situ from condensation of γ-silyl-substituted enals with vinylogous amides. The ensuing stereoselective ring closures are part of a tandem sequence that constitutes an aza-[3 + 3] annulation method for constructing 1,2-dihydropyridines. Several mechanisms for the formal 1,7-hydrogen shift of these 1-azatrienes were evaluated computationally.

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds.

A stereoselective cyclization between alkylidene oxindoles and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (as low as 5 mol %) to afford spiro[3,3'-oxindole-1-pyrrolines] in excellent yield (up to 99%) and diastereoselectivity (up to 99:1). Using a chiral scandium(III)-indapybox/BArF complex affords enantioenriched spirooxindole-1-pyrrolines where a ligand-induced reversal of diastereoselectivity is observed. This methodology is further demonstrated for the synthesis of pyrrolines from malonate alkylidene and coumarin derivatives.