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Since its discovery in 1938, hydroformylation has been thoroughly investigated and broadly applied in industry (>107metric ton yearly). However, the ability to precisely control its regioselectivity with well-established Rh- or Co-catalysts has thus far proven elusive, thereby limiting access to many synthetically valuable aldehydes. Pd-catalysts represent an appealing alternative, yet their use remains sparse due to undesired side-processes. Here, we report a highly selective and exceptionally active catalyst system that is driven by a novel activation strategy and features a unique Pd(I)–Pd(I) mechanism, involving an iodide-assisted binuclear step to release the product. This method enables β-selective hydroformylation of a large range of alkenes and alkynes, including sensitive starting materials. Its utility is demonstrated in the synthesis of antiobesity drug Rimonabant and anti-HIV agent PNU-32945. In a broader context, the new mechanistic understanding enables the development of other carbonylation reactions of high importance to chemical industry.

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 F3C-substituted alkenes is introduced. These processes, unlike the previously reported strategies, are applicable to alkyl as well as aryl substituted substrates, afford allyl boronates bearing a difluoroalkene moiety (up to 98% yield and 95:5 er). Second, the corresponding silyl substitutions, the first reported cases of their kind, are presented (up to 94% yield and 97:3 er). Third, experimental and computational (DFT) investigations are described that shed light on key mechanistic aspects of the catalytic processes. Evidence (X-ray structures of Cu–alkyl intermediates and kinetic studies) is put forth illustrating that the initial Cu–boryl and Cu–silyl addition is significantly faster than the ensuing Cu–F elimination, and that the latter step can be facilitated by either a mild Lewis acid (e.g., a Li or Na cation) or a nucleophilic promoter (e.g., an alkoxide). These findings together with DFT studies demonstrate that Cu–F β-elimination probably proceeds with anti-stereochemistry. Representative cases of ways through which the new mechanistic understanding may be used to rationalize previously disclosed findings, significantly improve a transformation, or develop new diastereo- and enantioselective catalytic methods are provided. For example, an explanation is provided regarding why bisphosphine–Cu complexes do not efficiently promote boryl substitutions with aryl-substituted substrates, but the corresponding silyl substitutions are facile, and how the size of a ligand can impact regioselectivity and efficiency.

Control of enantioselectivity remains a major challenge in radical chemistry. The emergence of metalloradical catalysis (MRC) offers a conceptually new strategy for addressing this and other outstanding issues. Through the employment of D2-symmetric chiral amidoporphyrins as the supporting ligands, Co(II)-based MRC has enabled the development of new catalytic systems for asymmetric radical transformations with a unique profile of reactivity and selectivity. With the support of new-generation HuPhyrin chiral ligands whose cavity environment can be fine-tuned, the Co-centered d-radicals enable to address challenging issues that require exquisite control of fundamental radical processes. As showcased with asymmetric 1,5-C–H amination of sulfamoyl azides, the enantiocontrol of which has proven difficult, the judicious use of HuPhyrin ligand by tuning the bridge length and other remote nonchiral elements allows for controlling both the degree and sense of asymmetric induction in a systematic manner. This effort leads to successful development of new Co(II)-based catalytic systems that are highly effective for enantiodivergent radical 1,5-C–H amination, producing both enantiomers of the strained five-membered cyclic sulfamides with excellent enantioselectivities. Detailed deuterium-labeling studies, together with DFT computation, have revealed an unprecedented mode of asymmetric induction that consists of enantiodifferentiative H-atom abstraction and stereoretentive radical substitution.

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 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 utilized 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 SN2′- and enantioselective allylic substitution method involving a mild alkylzinc halide reagent; and (3) a diastereoselective [3+2]-cycloaddition to assemble the polycyclic structure of a guanidyl polycyclic natural product.

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/Eratio. 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).

Catalytic enantioselective boron–hydride additions to 1,3-enynes, which afford allenyl–B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine–Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl–B(pin) products were generated in 52–80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8–99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu–C cleavage. This is particularly a problem when trapping of the Cu–allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron–hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron–hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl–B(pin) isomer may be generated (25–96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl–B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl–B(pin) compound might proceed with high stereospecificity (e.g., phosphine–Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine–Cu-catalyzed allylic substitution).

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:Zratio, and 86:14–98:2 enantiomeric ratio (er). Reactions with a silyl-protected propargyl-B(pin) compound led to the formation of the corresponding silyl-allenyl products in 53–89% yield, 69–96% SN2″ selectivity, 98:2 to >98:2 E:Zratio, and 94:6–98:2 er. Insight regarding several of the unique mechanistic attributes of the catalytic process was obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicate that cationic π-allyl-Cu complexes are likely intermediates, clarifying the role of the s-cisand s-transconformers of the intermediate organocopper species and their impact on E:Zselectivity and enantioselectivity. The utility of the approach is demonstrated by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products have been converted catalytically and chemoselectively to several useful derivatives.

Catalytic transformations of α-amino C–H bonds to afford valuable enantiomerically enriched α-substituted amines, entities that are prevalent in pharmaceuticals and bioactive natural products, have been developed. Typically, such processes are carried out under oxidative conditions and require precious metal-based catalysts. Here, we disclose a strategy for an enantioselective union of N-alkylamines and α,β-unsaturated compounds, performed under redox-neutral conditions, and promoted through concerted action of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg–PyBOX complex. Thus, a wide variety of β-amino carbonyl compounds may be synthesized, with complete atom economy, through stereoselective reaction of an in situ-generated enantiomerically enriched Mg-enolate and an appropriate electrophile.

A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that an 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 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.

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 development of catalyst-controlled stereoselective olefin metathesis processes has been a pivotal recent advance in chemistry. The incorporation of appropriate ligands within complexes based on molybdenum, tungsten and ruthenium has led to reactivity and selectivity levels that were previously inaccessible. Here we show that molybdenum monoaryloxide chloride complexes furnish higher-energy (Z) isomers of trifluoromethyl-substituted alkenes through cross-metathesis reactions with the commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be effected with substantially improved efficiency and Z selectivity. The use of such molybdenum monoaryloxide chloride complexes enables the synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. The origins of the activity and selectivity levels observed, which contradict previously proposed principles, are elucidated with the aid of density functional theory calculations.

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.

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.

Immer abwechselnd: Rutheniumkomplexe mit asymmetrischen zweizähnigen Phosphanliganden, die zwei unterschiedlich große Substituenten enthalten (grüne Kugeln), setzen Norbornen und Cycloocten in der Ringöffnungsmetathese‐Polymerisation (ROMP) zu einem vollständig alternierenden Copolymer um. Das E/Z‐Verhältnis lässt sich durch Variation des Raumbedarfs des Arensulfonatliganden (blaues Rechteck) systematisch verändern.

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