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The first examples of cross-metathesis between two different allenes is disclosed. First- and second-generation Ru complexes were found to be ineffective, at most affording only oligomeric products. The exception was a first-generation complex bearing a bidentate phenyl isopropoxy ligand (i.e., PCy3 is not released upon initiation), reactions with which afforded a 1,3-disubstituted allenyl boronate in 22% yield. On the basis of mechanistic studies designed to gain deeper understanding of the reasons for the ineffectiveness of different Ru catalysts, it was discovered that phosphine-free Ru-CAAC complexes have the steric and electronic attributes to be highly effective. The results of these investigations pave the way for development of additional olefin metathesis reactions that generate allenes.

Stereochemically defined organofluorine compounds are vital to drug discovery and many applicable catalytic strategies have been introduced for accessing these entities stereoselectively. One approach entails incorporation of a fluorine atom (C-F bond formation) or an organofluorine moiety (e.g., CF

Molybdenum and tungsten oxo 2-adamantylidene (Adene) complexes that contain two nonafluoro-tert-butoxide (ORF9) ligands have been prepared through addition of 2-methylene- or 2-ethylideneadamantane...

Trisubstituted alkenyl fluorides are needed for research in biological chemistry, drug discovery, agrochemical development, and materials science. Among other applications, these entities are secondary amide bond mimics in one stereoisomeric form and induce a peptide turn in the other. Despite notable progress, however, many stereochemically defined trisubstituted fluoro-alkenes either cannot be prepared efficiently, or can be accessed in only one isomeric form. Here, we outline a general solution to this problem by first unveiling a practical, widely applicable, and catalytic strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. This has been accomplished by cross-metathesis between two trisubstituted olefins, one of which is a purchasable but scarcely utilized trihalo alkene. Subsequent cross-coupling then be used to generate an assortment of trisubstituted alkenyl fluorides. The importance of the advance is highlighted by syntheses of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer).

Ethylene is the byproduct of olefin metathesis reactions that involve one or more terminal alkenes. Its volatility is one reason why many cross-metathesis or ring-closing metathesis processes, which are reversible transformations, are efficient. However, because ethylene can be converted to a methylidene complex, which is a highly reactive but relatively unstable species, its concentration can impact olefin metathesis in other ways. In some cases, introducing excess ethylene can increase reaction rate owing to faster catalyst initiation. Ethylene and a derived methylidene complex can also advantageously inhibit substrate or product homocoupling, and/or divert a less selective pathway. In other instances, a methylidene's low stability and high activity may lead to erosion of efficiency and/or kinetic selectivity, making it preferable that ethylene is removed while being generated. If methylidene decomposition is so fast that there is little or no product formation, it is best that ethylene and methylidene complex formation is avoided altogether. This is accomplished by the use of di- or trisubstituted alkenes in stereoretentive processes, which includes adopting methylene capping strategy. Here, we analyze the different scenarios through which ethylene and the involvement of methylidene complexes can be manipulated and managed so that an olefin metathesis reaction may occur more efficiently and/or more stereoselectively.

A copper-based complex that contains a sulfonate N-heterocyclic carbene ligand was first reported 15 years ago. Since then, these organometallic entities have proven to be uniquely effective in catalyzing an assortment of enantioselective transformations, including allylic substitutions, conjugate additions, proto-boryl additions to alkenes, boryl and silyl substitutions, hydride-allyl additions to alkenyl boronates, and additions of boron-containing allyl moieties to N-H ketimines. In this review article, we detail the shortcomings in the state-of-the-art that fueled the development of this air stable ligand class, members of which can be prepared on multigram scale. For each reaction type, when relevant, the prior art at the time of the advance involving sulfonate NHC-Cu catalysts and/or subsequent key developments are briefly analyzed, and the relevance of the advance to efficient and enantioselective total or formal synthesis of biologically active molecules is underscored. Mechanistic analysis of the structural attributes of sulfonate NHC-Cu catalysts that are responsible for their ability to facilitate transformations with high efficiency as well as regio- and enantioselectivity are detailed. This review contains several formerly undisclosed methodological advances and mechanistic analyses, the latter of which constitute a revision of previously reported proposals.

Addition of 1 equiv of water to Mo­(CArp)­(ORF9)3 (Arp = p-methoxyphenyl; ORF9 = OC­(CF3)3) in the presence of 5% NEt3 (vs Mo) in THF led to the formation of Mo­(O)­(CHArp)­(ORF9)2(THF)2 in good yield. Mo­(O)­(CHArp)­(ORF9)2(THF)2 reacts with 2 equiv of LiOHMT (OHMT = O-2,6-mesityl2C6H3) at room temperature to yield Mo­(O)­(CHArp)­(OHMT)2 and with 2 equiv of NaOTPP (OTPP = 2,3,5,6-tetraphenylphenoxide) to yield Mo­(O)­(CHArp)­(OTPP)2. In the presence of TMEDA (2.5 equiv), Mo­(CR)­(ORF9)3 (R = Arp, mesityl, or t-Bu) reacts with 1 equiv of water to yield Mo­(O)­(CHR)­(ORF9)2(TMEDA) complexes, from which (when R = t-Bu) TMEDA is readily displaced by 2,2′-bipyridyl to give Mo­(O)­(CH-t-Bu)­(ORF9)2(bipy). Mo­(O)­(CH-t-Bu)­(ORF9)2(bipy) was converted into Mo­(O)­(CH-t-Bu)­Cl2(bipy) readily, from which Mo­(O)­(CH-t-Bu)­Cl­(OHMT)­(3-Brpy) (3-Brpy = 3-bromopyridine) and Mo­(O)­(CH-t-Bu)­Cl­(OHIPT)­(3-Brpy) (OHIPT = O-2,6-(2,4,6-i-Pr3C6H2)2C6H3) were prepared. X-ray studies were carried out on Mo­(O)­(CHArp)­(ORF9)2(THF)2, Mo­(O)­(CH-t-Bu)­(ORF9)2(TMEDA), Mo­(O)­(CHArp)­(OTPP)2, Mo­(O)­(CH-t-Bu)­Cl­(OHMT)­(3-Brpy), and Mo­(O)­(CH-t-Bu)­Cl­(OHIPT)­(3-Brpy).

A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic α-tertiary NH2 -amines is introduced. Easy-to-synthesize and robust N-silyl ketimines are converted to NH-ketimines in situ, which then react with a Z-allyl boronate. Transformations are promoted by a readily accessible l-threonine-derived aminophenol-based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl-, a chloro-, or a bromo-substituted Z-alkene, can either be purchased or prepared by catalytic stereoretentive cross-metathesis. What is more, Z-trisubstituted allyl boronates may be used. Various chemo-, regio-, and diastereoselective transformations of the α-tertiary homoallylic NH2 -amine products highlight the utility of the approach; this includes diastereo- and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of a wide range of bioactive organic molecules. More specifically, Z-Chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl–B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may then be used in the central transformation of the entire approach, namely, an α-, and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multi-gram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F(3)C-substituted alkene can be prepared with similarly high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can also be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct and protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, and generates mycothiazole in 14.5% overall yield.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

Synthesis of complex bioactive molecules is substantially facilitated by transformations that efficiently and stereoselectively generate polyfunctional compounds. Designing such processes is hardly straightforward, however, especially when the desired route runs counter to the inherently favored reactivity profiles. Furthermore, in addition to being efficient and stereoselective, it is crucial that the products generated can be easily and stereodivergently modified. Here, we introduce a catalytic process that delivers a versatile and otherwise difficult-to-access organoboron entities by combining an allenylboronate, a hydride, and an allylic phosphate. Two unique selectivity problems had to be solved: avoiding rapid side reaction of a Cu–H complex with an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly utilised boron–copper exchange. The utility of the approach is demonstrated by applications to concise preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and enantioselective synthesis and structure confirmation of netamine C, a member of a family of anti-tumor and anti-malarial natural products. Completion of the latter routes required the following noteworthy developments: 1) A two-step all-catalytic sequence for conversion of a terminal alkene to a monosubstituted alkyne. 2) A catalytic S(N)2’- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent. 3) A diastereoselective [3+2]-cycloaddition protocol to assemble to polycyclic structure of a guanidyl polycyclic natural product.

The first catalytic method for diastereo- and enantioselective synthesis of allylic boronates bearing a Z-trisubstituted alkenyl fluoride is disclosed. Boryl substitution is performed with either a Z- or E-allyldifluoride and is catalyzed by bisphosphine/Cu complexes, affording products in up to 99 % yield with >98:2 Z/E selectivity and 99:1 enantiomeric ratio. A variety of subsequent modifications are feasible, and notable examples are diastereoselective additions to aldehydes/aldimines to access homoallylic alcohols/amines containing a fluorosubstituted stereogenic quaternary center.

Grafting a molybdenum oxo alkylidene on silica (partially dehydroxylated at 700 °C) affords the first example of a well-defined silica-supported Mo oxo alkylidene, which is an analogue of the putative active sites in heterogeneous Mo-based metathesis catalysts. In contrast to its tungsten analogue, which shows poor activity towards terminal olefins because of the formation of a stable off-cycle metallacyclobutane intermediate, the Mo catalyst shows high metathesis activity for both terminal and internal olefins that is consistent with the lower stability of Mo metallacyclobutane intermediates. This Mo oxo metathesis catalyst also outperforms its corresponding neutral silica-supported Mo and W imido analogues.

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for preparation of di- or trisubstituted alkenyl nitriles. Related approaches which are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-disubstituted cyano-substituted alkenes or their corresponding trisubstituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide (MAP) or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy-to-apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to synthesis of biologically active compounds., Graphical Abstract

The first broadly applicable strategy for SN2″-selective and enantioselective catalytic substitution is disclosed. Transformations are promoted by 5.0 mol% of a sulfonate-containing NHC-Cu complex (NHC = N-heterocyclic carbene), and are carried out in the presence of commercially available allenyl-B(pin) (pin = pinacolato) or a readily accessible silyl-protected propargyl-B(pin). Acyclic, or aryl-, heteroaryl-, and alkyl-substituted penta-2,4-dienyl phosphates, as well as those bearing either only 1,2-disubstituted olefins or a 1,2-disubstituted and a trisubstituted alkene were found to be suitable starting materials. Cyclic dienyl phosphates may also serve as substrates. The products containing, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moiety (from reactions with allenyl-B(pin)) were obtained in 51–82% yield, 84–97% SN2″ selectivity, 89:11–97:3 E:Z ratio, and 86:14–98:2 enantiomeric ratio (er). Reactions with a silyl-protected propargyl-B(pin) compound led to the formation ...

A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of β,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52–96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong C=N→B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70–96% yield and 92:8 to >98:2 dr – in either diastereomeric form – by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.

The first catalytic, broadly applicable, efficient, γ-, diastereo-, and enantioselective method for addition of O-substituted allyl–B(pin) compounds to phosphinoylimines (MEM = methoxyethoxymethyl, pin = pinacolato) is presented. The identity of the most effective catalyst and the optimal protecting group for the organoboron reagent were determined by consideration of the steric and electronic requirements at different stages of the catalytic cycle, namely, the generation of the chiral allylboronate, the subsequent 1,3-borotropic shift, and the addition step. Aryl-, heteroaryl-, alkenyl- and alkyl-substituted vicinal phosphinoylamido MEM-ethers were thus accessed in 57–92% yield, 89:11 to >98:2 γ:α selectivity, 76:24–97:3 diastereomeric ratio, and 90:10–99:1 enantiomeric ratio. The method is scalable, and the phosphinoyl and MEM groups may be removed selectively or simultaneously. Utility is highlighted by enantioselective synthesis of an NK-1 receptor antagonist.

Catalytic enantioselective methods are introduced that allow access to a variety of allyl boronates and silanes that contain a difluoroalkene unit; the resulting products may be used for the preparation of organofluorine compounds in high enantiomeric purity. Furthermore, a number of key mechanistic aspects of the transformations have been investigated and analyzed. Thus, first, an NHC-Cu-catalyzed method for boryl substitution with F

An emerging area of research in chemistry requires that we learn how to manage the characteristics of a pair of co-catalysts so that a transformation proceeds as we wish it to. These are processes during which one catalyst first generates a non-isolable intermediate, which then in situ undergoes a reaction that is promoted by a

Reactions between (Z)-XCH═CHX, where X = Cl, CF3, CN, and Mo(N-t-Bu)(CH-t-Bu)(OHIPT)Cl(PPh2Me) (OHIPT = O-2,6-(2,4,6-i-Pr3C6H2)2C6H3) produce Mo(N-t-Bu)(CHX)(OHIPT)Cl(PPh2Me) complexes. Addition of 2,2′-bipyridyl (Bipy) yields Mo(N-t-Bu)(CHX)(OHIPT)Cl(Bipy) complexes, which could be isolated and structurally characterized. The reaction between Mo(N-t-Bu)(CH-t-Bu)(OHMT)Cl(PPh2Me) (OHMT = O-2,6-(2,4,6-Me3C6H2)2C6H3) and (Z)-ClCH═CHCl in the presence of Bipy produces a mixture that contains both Mo(N-t-Bu)(CHCl)(OHMT)Cl(PPh2Me) and Mo(N-t-Bu)(CHCl)(OHMT)Cl(Bipy), but the relatively insoluble product that crystallizes from toluene-d8 is the phosphoniomethylidene complex [Mo(N-t-Bu)(CHPPh2Me)(OHMT)Cl(Bipy)]Cl. The Mo(N-t-Bu)(CHX)(OHIPT)Cl(PPh2Me) complexes (X = Cl, CF3) were confirmed to initiate the stereoselective cross-metathesis between (Z)-5-decene and (Z)-XCH═CHX.

Addition of one equiv of water to Mo(CAr)[OCMe(CF3)2]3(1,2-dimethoxyethane) (2, Ar = o-(OMe)C6H4) in the presence of PPhMe2 leads to formation of Mo(O)(CHAr)[OCMe(CF3)2]2(PPhMe2) (3(PPhMe2)) in 34% yield. Addition of one equiv of water alone to 2 produces the dimeric alkylidyne hydroxide complex, {Mo(CAr)[OCMe(CF3)2]2(μ-OH)}2(dme) (4(dme)) in which each bridging hydroxide proton points toward an oxygen atom in an arylmethoxy group. Addition of PMe3 to 4(dme) gives the alkylidene oxo complex, (3(PMe3)), an analogue of 3(PPhMe2) (95% conversion, 66% isolated). Treatment of 3(PMe3) with two equiv of HCl gave Mo(O)(CHAr)Cl2(PMe3) (5), which upon addition of LiO-2,6-(2,4,6-i-Pr3C6H2)2C6H3 (LiOHIPT) gave Mo(O)(CHAr)(OHIPT)Cl(PMe3) (6). Compound 6 in the presence of B(C6F5)3 will initiate the ring-opening metathesis polymerization of cyclooctene, 5,6-dicarbomethoxynorbornadiene (DCMNBD), and rac-5,6-dicarbomethoxynorbornene (DCMNBE), and the homocoupling of 1-decene to 9-octadecene. The poly(DCMNBD) has a cis,syndiotactic structure, whereas poly(DCMNBE) has a cis,syndiotactic,alt structure. X-ray structures were obtained for 3(PPhMe2), 4(dme), and 6.

A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that intimate understanding of this distinction provides ways for addressing limitations in reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic enantioselective Cu–boryl addition to alkenes as the model process, we have been able to elucidate several key mechanistic principles. We show that higher electrophile concentration can lead to elevated enantioselectivity; this is because diastereoselective Cu–H elimination may be avoided and/or achiral Cu–boryl intermediates can be converted to allyl–B(pin) rather than add to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the deleterious influence of achiral Cu–alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper–hydride elimination is faster with an achiral Cu-alkyl species.

The first enantioselective total synthesis of (−)-deoxoapodine is described. Our synthesis of this hexacyclic aspidosperma alkaloid includes an efficient molybdenum-catalyzed enantioselective ring-closing metathesis reaction for the desymmetrization of an advanced intermediate that introduces the C5-quaternary stereocenter. After C21-oxygenation, the pentacyclic core was accessed by electrophilic C19-amide activation and transannular spirocyclization. A biogenetically inspired dehydrative C6-etherification reaction proved highly effective to secure the F-ring and the fourth contiguous stereocenter of (−)-deoxoapodine with complete stereochemical control., NIH-NIGMS (grant no. GM074825)

In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.

There are many biologically active organic molecules that contain one or more nitrogen-containing moieties, and broadly applicable and efficient catalytic transformations that deliver them diastereoselectively and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (for example, from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N-H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N-H ketimine, a monosubstituted allene and B2(pin)2, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. The utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models developed with the aid of density functional theory calculations, which account for the observed trends and levels of enantioselectivity, are presented.

The investigations disclosed offer insight regarding several key features of Ru-based catecholthiolate olefin metathesis catalysts. Factors influencing the facility with which the two anionic ligands undergo exchange and those that affect the rates of catalyst release are elucidated by examination of more than a dozen new complexes. These studies shed light on how different chelating groups can influence Ru–S bond strength and, as a result, the facility of catecholthiolate rotation. The trans influence series ether < ester ≈ iodide < amine ≈ thioether ≈ olefin < isonitrile ≈ phosphite has been established through X-ray structural analysis and shown to correlate well with the barrier for catecholthiolate rotation (trans effect) determined by variable-temperature NMR experiments and computational studies (DFT). It is found that, apart from electronic factors, chelate geometry has a more notable effect on the rate of catalyst release (five- vs six-membered chelate ring and mono- vs bidentate ligand). Polytop...

Reactions between Mo(N-t-Bu)(2)(CH(2)-t-Bu)(2) or Mo(NAdamantyl)(2)(CH(2)CMe(2)Ph)(2) and 3 equiv of HCl in the presence of 1 equiv of PPh(2)Me yield Mo(NR)(CHR’)(PPh(2)Me)Cl(2) complexes, from which Mo(NR)(CHR’)(PPh(2)Me)(OAr)Cl complexes (OAr = a 2,6-terphenoxide) can be prepared. The Mo(NR)(CHR’)(PPh(2)Me)(OAr)Cl complexes were evaluated as cross-metathesis catalysts between cyclooctene and Z-1,2-dichloroethylene. The efficiencies of the test reaction for complexes in which OAr = OTPP, OHMT, OHIPT, or OHTBT (where OTPP is 2,3,5,6-tetraphenylphenoxide, OHMT is hexamethylterphenoxide, OHIPT is hexaisopropylterphenoxide, and OHTBT is hexa-t-butylterphenoxide) maximize when OAr is OHMT or OHIPT. Mo(N-t-Bu)(CH-t-Bu)(PPh(2)Me)Cl(2) is essentially inactive for the reaction between cyclooctene and Z-1,2-dichloroethylene. X-ray structural studies were carried out on Mo(NAd)(CHCMe(2)Ph)(PPh(2)Me)Cl(2), Mo(N-t-Bu)(CH-t-Bu)(PPh(2)Me)(OHMT)Cl, Mo(NAd)(CHCMe(2)Ph)(Cl)(OHTBT)(PMe(3)), and [Mo(NAd)(CHCMe(2)Ph)(PMe(3))(Cl)](2)(μ-O), the product of the reaction between Mo(NAd)(CHCMe(2)Ph)(Cl)(OHTBT)(PMe(3)) and 0.5 equiv of water.

We disclose the results of an investigation designed to generate insight regarding the differences in the electronic and steric attributes of C–F, C–Cl, and C–Br bonds. Mechanistic insight has been gleaned by analysis of variations in enantioselectivity, regarding the ability of electrostatic contact between a halomethyl moiety and a catalyst’s ammonium group as opposed to factors lowering steric repulsion and/or dipole minimization. In the process, valuable catalytic and enantioselective methods have been developed for transforming a wide range of trihalomethyl (halogen = Cl or Br), dihalomethyl or monohalomethyl (halogen = F, Cl, or Br) ketones to the corresponding tertiary homoallylic alcohols. By exploiting electrostatic attraction between a halomethyl moiety and the catalyst’s ammonium moiety and steric factors, high enantioselectivity was attained in many instances. Reactions can be performed with 0.5–5.0 mol % of an in situ generated boryl–ammonium catalyst, affording products in 42–99% yield, and up to >99:1 enantiomeric ratio. Not only are there no existing protocols for accessing the great majority of the resulting products enantioselectively, in some cases there are hardly any instances of a catalytic enantioselective addition of a carbon-based nucleophile (e.g., one enzyme-catalyzed aldol addition involving trichloromethyl ketones, and none with dichloromethyl, tribromomethyl, or dibromomethyl ketones). The approach is scalable and offers an expeditious route to enantioselective synthesis of versatile and otherwise difficult-to-access aldehydes that bear an α-halo-substituted quaternary carbon stereogenic center as well as an assortment of 2,2-disubstituted epoxides that also bear an easily modifiable alkene. Tertiary homoallylic alcohols containing a triazole and a halomethyl moiety, structural units relevant to drug development, may also be accessed efficiently and with exceptional enantioselectivity.

Angewandte Chemie. International Edition, 58 (34), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

Despite notable progress, olefin metathesis methods for preparation of ( Z)-α,β-unsaturated carbonyl compounds, applicable to the synthesis of a large variety of bioactive molecules, remain scarce. Especially desirable are transformations that can be promoted by ruthenium-based catalysts, as such entities would allow direct access to carboxylic esters and amides, or acids (in contrast to molybdenum- or tungsten-based alkylidenes). Here, we detail how, based on the mechanistic insight obtained through computational and experimental studies, a readily accessible ruthenium catechothiolate complex was found that may be used to generate many α,β-unsaturated carbonyl compounds in up to 81% yield and ≥98:2 Z/ E ratio. We show that through the use of a complex bearing an unsaturated N-heterocyclic carbene (NHC) ligand, for the first time, products derived from the more electron-deficient esters, acids, and Weinreb amides (vs primary or secondary amides) can be synthesized efficiently and with high stereochemical control. The importance of the new advance to synthesis of bioactive compounds is illustrated through two representative applications: an eight-step, 15% overall yield, and completely Z-selective route leading to an intermediate that may be used in synthesis of stagonolide E (vs 11 steps, 4% overall yield and 91% Z, previously), and a five-step, 25% overall yield sequence to access a precursor to dihydrocompactin (vs 13 steps and 5% overall yield, formerly).

An operationally simple in situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic Z- and E-selective olefin metathesis is introduced. We demonstrate that, prior to the addition of a sensitive Mo- or Ru-based complex, treatment of a hydroxy- or a carboxylic acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip)(2) (pin = pinacolato, trip = 2,4,6-tri(iso-propyl)phenyl) for 15 minutes is sufficient for efficient generation of a desired product. Routine workup leads to quantitative deprotection. A range of stereochemically defined Z- or E-alkenyl chlorides, bromides, fluorides, and boronates or Z-trifluoromethyl-substituted alkenes with a hydroxy- or a carboxylic acid group were thus prepared in 51–97% yield and 93% to >98% stereoselectivity. The substrates, HB(pin), and cross-partners were used as received. We also show that, regardless of whether a polar functional unit is present or not, a small amount of HB(pin) (e.g., 10 mol %) may be used to remove residual water, significantly enhancing efficiency (i.e., lower catalyst loading).

The first broadly applicable strategy for S

Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates. Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce and are confined to reactions promoted by a phosphine-copper catalyst (with an alkyl Grignard reagent, dialkylzinc or trialkylaluminium compounds), a diene-iridium catalyst (with arylboroxines), or a bisphosphine-cobalt catalyst (with monosilyl-acetylenes). 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position. It is unclear why certain catalysts favour bond formation at C6, and-although there are a small number of catalytic enantioselective conjugate allyl additions-related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl-boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (-)-equisetin.

A set of broadly applicable methods for efficient catalytic additions of easy-to-handle allyl-B(pin) (pin=pinacolato) compounds to ketones and acyclic α-ketoesters was developed. Accordingly, a large array of tertiary alcohols can be obtained in 60 to >98 % yield and up to 99:1 enantiomeric ratio. At the heart of this development is rational alteration of the structures of the small-molecule aminophenol-based catalysts. Notably, with ketones, increasing the size of a catalyst moiety (tBu to SiPh3 ) results in much higher enantioselectivity. With α-ketoesters, on the other hand, not only does the opposite hold true, since Me substitution leads to substantially higher enantioselectivity, but the sense of the selectivity is reversed as well.

Organofluorine compounds are central to modern chemistry, and broadly applicable transformations that generate them efficiently and enantioselectively are in much demand. Here we introduce efficient catalytic methods for the addition of allyl and allenyl organoboron reagents to fluorine-substituted ketones. These reactions are facilitated by readily and inexpensively available catalysts and deliver versatile and otherwise difficult-to-access tertiary homoallylic alcohols in up to 98% yield and >99:1 enantiomeric ratio. Utility is highlighted by a concise enantioselective approach to the synthesis of the antiparasitic drug fluralaner (Bravecto, presently sold as the racemate). Different forms of ammonium-organofluorine interactions play a key role in the control of enantioselectivity. The greater understanding of various non-bonding interactions afforded by these studies should facilitate the future development of transformations that involve fluoroorganic entities.

Readily accessible and easy-to-handle Ru complexes capable of generating all-Z polynorbornene and polynorbornadiene by ring-opening metathesis polymerization (ROMP) with controllable selectivity, ranging from ≈50 to ≥95 % syndiotactic, are introduced. It is demonstrated that the rate of non-metathesis based polytopal isomerization and levels of syndiotacticity may be fine-tuned by the adjustment of monomer concentration and catalyst's steric and electronic characteristics.

Catalytic allylboron additions to aldimines are presented for which small amounts of Zn(OMe)2 serve as the co-catalyst to accelerate allyl exchange and 1,3-borotropic shift processes. Low-yielding and moderately α- and diastereoselective reactions are thus turned into highly efficient γ-, diastereo-, and enantioselective transformations that exhibit considerable scope.

An enduring question in olefin metathesis is that reactions carried out with widely accessible Ru dichloro complexes, which typically favor E alkenes, generate Z isomers preferentially when substrates bearing a smaller substituent are used; Z enol ethers, alkenyl sulfides, 1,3-enynes, alkenyl halides, or alkenyl cyanides can be prepared reliably with reasonable efficiency and selectivity. Transformations thus proceed via the more hindered syn-substituted metallacyclobutanes, which is mystifying because catalyst features implemented in the more recently developed and broadly applicable Z-selective catalysts are absent in the Ru dichloro systems. Herein, we describe experimental and computational investigations that offer a plausible rationale for these puzzling selectivity trends. The following will be demonstrated. (1) Kinetic Z selectivity depends on the relative barrier for olefin association/dissociation versus metallacyclobutane formation/cleavage. There can be appreciable stereochemical control when ...