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The development of bimolecular homolytic substitution (S H 2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism 1-8 . Biomimetic 9,10 S H 2 catalysis can be used to merge common feedstock chemicals-such as alcohols, acids and halides-in various permutations for the construction of a single C(sp 3 )-C(sp 3 ) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C(sp 3 )-C(sp 3 ) bonds, greatly accelerating access to complex molecules and drug-like chemical space 11 . However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways 12,13 . Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C(sp 3 )-rich molecules and defines a distinct mechanistic approach for alkene dialkylation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step. Carbohydroxylations of olefins represent a family of reactivity that furnish structurally complex alcohols. While examples of this type of three-component coupling have been reported, catalytic asymmetric examples remain elusive. Here, we report an enzyme-catalyzed asymmetric carbohydroxylation of alkenes catalyzed by flavin-dependent "ene"-reductases to produce enantioenriched tertiary alcohols. Seven rounds of protein engineering reshape the enzyme's active site to increase activity and enantioselectivity. Mechanistic studies suggest that C-O bond formation occurs via a 5-endo-trig cyclization with the pendant ketone to afford an α-oxy radical which is oxidized and hydrolyzed to form the product. This work demonstrates photoenzymatic reactions involving "ene"-reductases can terminate radicals via mechanisms other than hydrogen atom transfer, expanding their utility in chemical synthesis.

The catalytic epoxidation of small alkenes and allylic alcohols includes a wide range of valuable chemical applications, with many works describing vanadium complexes as suitable catalysts towards sustainable process chemistry. But, given the complexity of these mechanisms, it is not always easy to sort out efficient examples for streamlining sustainable processes and tuning product optimization. In this review, we provide an update on major works of tunable vanadium-catalyzed epoxidations, with a focus on sustainable optimization routes. After presenting the current mechanistic view on vanadium catalysts for small alkenes and allylic alcohols' epoxidation, we argue the key challenges in green process development by highlighting the value of updated kinetic and mechanistic studies, along with essential computational studies.

The triple ipso -defluoroetherification of (trifluoromethyl)alkenes with fluoroalkylated alcohols by C(sp 3 )-F bond cleavage is reported, delivering various fluoroalkylated orthoesters in high yields. This reaction is transition-metal free and gram-scalable, features mild reaction conditions, and tolerates diverse functional groups.

The addition of water to alkenes is an important method for the synthesis of alcohols, but the regioselectivity of acid-catalyzed hydration of terminal alkenes yields secondary alcohols according to Markovnikov's rule, making it difficult to obtain primary alcohols. Here we report a styrene monooxygenase that catalyzes the anti-Markovnikov hydration of the terminal aryl alkenes under anaerobic conditions. This hydration provides primary alcohols in good yields (up to 100 %), excellent anti-Markovnikov regioselectivity (>99 : 1), and good enantiomeric purity (60-83 % ee). Residues Asn46, Asp100, and Asn309 are essential for catalysis suggesting an acid-base mechanism with a carbanion-like intermediate that could account for the anti-Markovnikov regioselectivity. Our work reveals a new enzymatic tool with unusual regioselectivity based on the promiscuous catalytic activity of a monooxygenase., (© 2022 Wiley-VCH GmbH.)

The photoinitiated intramolecular hydroetherification of alkenols has been used to form C-O bonds, but the intermolecular hydroetherification of alkenes with alcohols remains an unsolved challenge. We herein report the visible-light-promoted 2-deoxyglycosylation of alcohols with glycals. The glycosylation reaction was completed within 2 min in a high quantum yield (ϕ=28.6). This method was suitable for a wide array of substrates and displayed good reaction yields and excellent stereoselectivity. The value of this protocol was further demonstrated by the iterative synthesis of 2-deoxyglycans with α-2-deoxyglycosidic linkages up to a 20-mer in length and digoxin with β-2-deoxyglycosidic linkages. Mechanistic studies indicated that this reaction involved a glycosyl radical cation intermediate and a photoinitiated chain process., (© 2022 Wiley-VCH GmbH.)

Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. Here, we report a strategy to access aliphatic esters from olefins through a photocatalyzed alkoxycarbonylation reaction. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding β-chloro esters in good yields. Additionally, a formal β-selective alkene alkoxycarbonylation is developed. Moreover, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed., (© 2021. The Author(s).)

The site-selective trifluoromethylation of aliphatic systems remains an important challenge. This work describes a light-driven, copper-mediated trifluoromethylation of O -alkyl thiocarbonates. The reaction provides broad functional group tolerance (e.g., alkyne, alkene, phenol, free alcohol, electron-rich and -deficient arenes), thereby offering orthogonality and practicality for trifluoromethylation. A radical organometallic mechanism is proposed.

Enzymes are increasingly explored for use in asymmetric synthesis 1-3 , but their applications are generally limited by the reactions available to naturally occurring enzymes. Recently, interest in photocatalysis 4 has spurred the discovery of novel reactivity from known enzymes 5 . However, so far photoinduced enzymatic catalysis 6 has not been used for the cross-coupling of two molecules. For example, the intermolecular coupling of alkenes with α-halo carbonyl compounds through a visible-light-induced radical hydroalkylation, which could provide access to important γ-chiral carbonyl compounds, has not yet been achieved by enzymes. The major challenges are the inherent poor photoreactivity of enzymes and the difficulty in achieving stereochemical control of the remote prochiral radical intermediate 7 . Here we report a visible-light-induced intermolecular radical hydroalkylation of terminal alkenes that does not occur naturally, catalysed by an 'ene' reductase using readily available α-halo carbonyl compounds as reactants. This method provides an efficient approach to the synthesis of various carbonyl compounds bearing a γ-stereocentre with excellent yields and enantioselectivities (up to 99 per cent yield with 99 per cent enantiomeric excess), which otherwise are difficult to access using chemocatalysis. Mechanistic studies suggest that the formation of the complex of the substrates (α-halo carbonyl compounds) and the 'ene' reductase triggers the enantioselective photoinduced radical reaction. Our work further expands the reactivity repertoire of biocatalytic, synthetically useful asymmetric transformations by the merger of photocatalysis and enzyme catalysis.

Dibromocyclopropanations are conventionally done by addition of dibromocarbene to alkenes under phase-transfer conditions in batch reactions using a strong base (50% NaOH (aq)), vigorous stirring and long reaction times. We have shown that cyclopropanation of unsaturated alcohols can be done under ambient conditions using continuous flow chemistry with 40% ( w / w ) NaOH (aq) as the base. The reactions were generally rapid; the yields were comparable to yields reported in the literature for the conventional batch reaction.

An efficient nickel-catalyzed removal of alkene protection group under mild condition with high functional group tolerance through chain walking process has been established. Not only phenolic ethers, but also alcoholic ethers can be tolerated with the retention of stereocenter adjacent to hydroxyl group. The new reaction brings the homoallyl group into a start of new type of protecting group., Competing Interests: The authors declare no conflict of interest.

Recently, CuH-catalyzed reductive coupling processes involving carbonyl compounds and imines have become attractive alternatives to traditional methods for stereoselective addition because of their ability to use readily accessible and stable olefins as surrogates for organometallic nucleophiles. However, the inability to use aldehydes, which usually reduce too rapidly in the presence of copper hydride complexes to be viable substrates, has been a major limitation. Shown here is that by exploiting relative concentration effects through kinetic control, this intrinsic reactivity can be inverted and the reductive coupling of 1,3-dienes with aldehydes achieved. Using this method, both aromatic and aliphatic aldehydes can be transformed into synthetically valuable homoallylic alcohols with high levels of diastereo- and enantioselectivities, and in the presence of many useful functional groups. Furthermore, using a combination of theoretical (DFT) and experimental methods, important mechanistic features of this reaction related to stereo- and chemoselectivities were uncovered., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pd-catalyzed C(sp 3 )-H activation of alcohol typically shows β-selectivity due to the required distance between the chelating atom in the attached directing group and the targeted C-H bonds. Herein we report the design of a hemilabile directing group which exploits the chelation of a readily removable benzyl ether moiety to direct γ- or δ-C-H carbonylation and olefination of alcohols. The utility of this approach is also demonstrated in the late-stage C-H functionalization of β-estradiol to rapidly prepare desired analogues that required multi-step syntheses with classical methods.

Enantioselective catalysis of excited-state photoreactions remains a substantial challenge in synthetic chemistry, and intermolecular photoreactions have proven especially difficult to conduct in a stereocontrolled fashion. Herein, we report a highly enantioselective intermolecular [2 + 2] cycloaddition of 3-alkoxyquinolones catalyzed by a chiral hydrogen-bonding iridium photosensitizer. Enantioselectivities as high as 99% ee were measured in reactions with a range of maleimides and other electron-deficient alkene reaction partners. An array of kinetic, spectroscopic, and computational studies supports a mechanism in which the photocatalyst and quinolone form a hydrogen-bonded complex to control selectivity, yet upon photoexcitation of this complex, energy transfer sensitization of maleimide is preferred. The sensitized maleimide then reacts with the hydrogen-bonded quinolone-photocatalyst complex to afford a highly enantioenriched cycloadduct. This finding contradicts a long-standing tenet of enantioselective photochemistry that held that stereoselective photoreactions require strong preassociation to the sensitized substrate in order to overcome the short lifetimes of electronically excited organic molecules. This system therefore suggests that a broader range of alternate design strategies for asymmetric photocatalysis might be possible.

We investigated potential biosynthetic pathways of long chain alkenols (LCAs), long chain alkyl diols (LCDs), and long chain hydroxy fatty acids (LCHFAs) in Nannochloropsis oceanica and Nannochloropsis gaditana, by combining culturing experiments with genomic and transcriptomic analyses. Incubation of Nannochloropsis spp. in the dark for 1 week led to significant increases in the cellular concentrations of LCAs and LCDs in both species. Consistently, 13C-labelled substrate experiments confirmed that both LCA and LCD were actively produced in the dark from C14-18 fatty acids by either condensation or elongation/hydroxylation, although no enzymatic evidence was found for the former pathway. Nannochloropsis spp. did, however, contain (i) multiple polyketide synthases (PKSs) including one type (PKS-Clade II) that might catalyze incomplete fatty acid elongations leading to the formation of 3-OH-fatty acids, (ii) 3-hydroxyacyl dehydratases (HADs), which can possibly form Δ2/Δ3 monounsaturated fatty acids, and (iii) fatty acid elongases (FAEs) that could elongate 3-OH-fatty acids and Δ2/Δ3 monounsaturated fatty acids to longer products. The enzymes responsible for reduction of the long chain fatty acids to LCDs and LCAs are, however, unclear. A putative wax ester synthase/acyl coenzyme A (acyl-CoA): diacylglycerol acyltransferase is likely to be involved in the esterification of LCAs and LCDs in the cell wall. Our data thus provide useful insights in predicting the biosynthetic pathways of LCAs and LCDs in phytoplankton suggesting a key role of FAE and PKS enzymes., (� The Author(s) 2019. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Herein we describe the development of a Pd-catalyzed enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of α-tertiary and α-secondary amines. The reaction affords a range of β-amino alcohols, after reduction of the aldehyde in situ, which contain a variety of functional groups in moderate yields and moderate to good enantioselectivities. These products can be readily oxidized to β-amino acids, valuable building blocks for the synthesis of biologically active compounds. Mechanistic studies indicate that the C-N bond formation occurs via a syn amino-palladation mechanism, an insight which may guide future reaction development given the limited number of enantioselective syntheses of α-tertiary amines.

Acyclic monoterpenes constitute a large and highly abundant class of secondary plant metabolites and are, therefore, attractive low-cost raw materials for the chemical industry. To date, numerous biocatalysts for their transformation are known, giving access to highly sought-after monoterpenoids. In view of the high selectivity associated with many of these reactions, the demand for enzymes generating commercially important target molecules is unabated. Here, linalool (de)hydratase-isomerase (Ldi, EC 4.2.1.127) from Castellaniella defragrans was examined for the regio- and stereoselective hydration of the acyclic monoterpene β-myrcene to ( S )-(+)-linalool. Expression of the native enzyme in Escherichia coli allowed for identification of bottlenecks limiting enzyme activity, which were investigated by mutating selected residues implied in enzyme assembly and function. Combining these analyses with the recently published 3D structures of Ldi highlighted the precisely coordinated reduction-oxidation state of two cysteine pairs in correct oligomeric assembly and the catalytic mechanism, respectively. Subcellular targeting studies upon fusion of Ldi to different signal sequences revealed the significance of periplasmic localization of the mature enzyme in the heterologous expression host. This study provides biochemical and mechanistic insight into the hydration of β-myrcene, a nonfunctionalized terpene, and emphasizes its potential for access to scarcely available but commercially interesting tertiary alcohols.

Sample configurations of distaminolyne A ( 1a ); isolated from the ascidians Pseudodistoma opacum and P. cereum , and collected at different sites in New Zealand, were investigated by two methods: Exciton coupled electronic circular dichroism (EC ECD) of the corresponding N , O -dibenzoyl derivative 1b ; and chiral reagent derivatization of 1a with ( S )- and ( R )-α-methoxyphenylacetic acid (MPA), followed by ¹H-NMR analysis. Configuration and optical purity of 1a (%ee) was found to vary depending on the geographic distribution of ascidian colonies. An improved method for preparing N , O -diarenoyl derivatives of 1a was optimized. The EC ECD method was found to be complementary to the MPA-NMR method at different ranges of %ee.

Tetrahydropyrans are abundantly found in marine natural products. The interesting biological properties of these compounds and their analogues make necessary the development of convenient procedures for their synthesis. In this paper, an atom economy access to tetrahydropyrans by intramolecular acid-mediated cyclization of silylated alkenols is described. p-TsOH has shown to be an efficient reagent to yield highly substituted tetrahydropyrans. Moreover, excellent diastereoselectivities are obtained both for unsubstituted and alkylsubstituted vinylsilyl alcohols. The methodology herein developed may potentially be applied to the synthesis of marine drugs derivatives.

Extension of a structure-activity relationship study of the antitumor cytotoxicity of lipidic dialkynylcarbinols (DACs) is envisaged by formal methinylogation of one of the ethyndiyl moieties of the DAC warhead into the corresponding allenylalkynylcarbinol (AllAC) counterpart. External AllACs were directly obtained by methinylation of the parent DACs with formaldehyde in either the racemic or scalemic series. Isomers containing external progargyl and propynyl motifs were also prepared. Internal AllACs were obtained as racemic statistical mixtures of stereoisomers in two steps from the key C 5 -DAC rac-TIPS-C≡C-CH(OH)-C≡CH and aldehydes. Kinetic resolution of the (S)-C 5 -DAC in 97 % ee and (R)-C 5 -DAC in 99 % ee was achieved by sequential lipase-mediated acetylation/hydrolysis using the Candida antartica lipase (Novozyme 435). The four internal AllAC stereoisomers were prepared by asymmetric methinylation with (R)- or (S)-diphenylprolinol as chiral auxiliary. Cytotoxicity assays on HCT116 cancer cells showed that the most active (eutomeric) external or internal AllAC exhibits an S configuration, a fatty chain length of n=12, and a 50 % inhibitory concentration IC 50 ≈1.0 μm., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a Rh-catalyst for accessing olefins from primary alcohols by a C-C bond cleavage that results in dehomologation. This functional group interconversion proceeds by an oxidation-dehydroformylation enabled by N, N-dimethylacrylamide as a sacrificial acceptor of hydrogen gas. Alcohols with diverse functionality and structure undergo oxidative dehydroxymethylation to access the corresponding olefins. Our catalyst protocol enables a two-step semisynthesis of (+)-yohimbenone and dehomologation of feedstock olefins.

Two new polyols, (2E,4E)-octa-2,4-diene-1,6,7-triol (1) and (E)-7,8-dihydroxyoct-5-en-2-one (2) were isolated from cultures of the basidiomycete Daedaleopsis tricolor. Their structures were elucidated by spectroscopic methods including extensive 2D NMR techniques. Two compounds showed no significant activity against five human cancer cell lines.

This Perspective describes the development of a family of copper(II)-catalyzed alkene difunctionalization reactions that enable stereoselective addition of amine derivatives and alcohols onto pendant unactivated alkenes to provide a range of valuable saturated nitrogen and oxygen heterocycles. 2-Vinylanilines and related substrates undergo alternative oxidative amination or allylic amination pathways, and these reactions will also be discussed. The involvement of both polar and radical steps in the reaction mechanisms have been implicated. Major product formation is a function of the lowest energy pathway, which in turn is a function of structural aspects of the various reaction components.

The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years. Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon-hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials. Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon-hydrogen oxidation of simple alkenes with cyclic or terminal double bonds. However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen-based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules.

In this report, we describe the generation of remote allylic quaternary stereocenters β, γ, and δ relative to a carbonyl in high enantioselectivity. We utilize a redox-relay Heck reaction between alkenyl triflates and acyclic trisubstituted alkenols of varying chain-lengths. A wide array of terminal (E)-alkenyl triflates are suitable for this process. The utility of this functionalization is validated further by conversion of the products, via simple organic processes to access remotely functionalized chiral tertiary acid, amine, and alcohol products.

An enantioselective redox-relay oxidative Heck arylation of 1,1-disubstituted alkenes to construct β-stereocenters was developed using a new pyridyl-oxazoline ligand. Various 1,2-diaryl carbonyl compounds were readily obtained in moderate yield and good to excellent enantioselectivity. Additionally, analysis of the reaction outcomes using multidimensional correlations revealed that enantioselectivity is tied to specific electronic features of the 1,1-disubstituted alkenol and the extent of polarizability of the ligand.

A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched α-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance.

The asymmetric dihydroxylation of olefins is of special interest due to the facile transformation of the chiral diol products into valuable derivatives. Rieske non-heme iron oxygenases (ROs) represent promising biocatalysts for this reaction as they can be engineered to efficiently catalyze the selective mono- and dihydroxylation of various olefins. The introduction of a single point mutation improved selectivities (≥95 %) and conversions (>99 %) towards selected alkenes. By modifying the size of one active site amino acid side chain, we were able to modulate the regio- and stereoselectivity of these enzymes. For distinct substrates, mutants displayed altered regioselectivities or even favored opposite enantiomers compared to the wild-type ROs, offering a sustainable approach for the oxyfunctionalization of a wide variety of structurally different olefins., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Malonoyl peroxide 1, prepared in a single step from the commercially available diacid, is an effective reagent for the anti-dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35-92%) with up to 13:1 anti-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed.

The use of NHCs for generating homoenolate species has gained widespread popularity in recent years. A number of highly stereoselective processes of NHC-homoenolates have emerged. Homoenolate reactions have also been employed as key steps in the total synthesis of a number of natural products. The use of compatible co-catalysts, improved NHC-catalyst design and the use of novel precursors for homoenolate generation are among the major developments in this area that were disclosed recently. This tutorial review organises and presents the advancements in this rapidly growing area of catalysis and in the process updates a previous account published in 2011 in this journal.

An efficient method for the synthesis of homoallylic alcohols with high enantioselectivities and anti-diastereoselectivities via an In(III)-catalyzed intermolecular glyoxylate-ene reaction has been developed. The geometrical isomers of alkenes were shown to have different reactivities. Only the isomers of the alkenes having a proton β-cis to the substituent reacted in this catalytic system.

An efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for synthesis of β-azido alcohols has been developed. The aerobic oxidative generation of azido radical employing air as the terminal oxidant is disclosed as the key process for this transformation. The reaction is appreciated by its broad substrate scope, inexpensive Mn-catalyst, high efficiency, easy operation under air, and mild conditions at room temperature. This chemistry provides a novel approach to high value-added β-azido alcohols, which are useful precursors of aziridines, β-amino alcohols, and other important N- and O-containing heterocyclic compounds. This chemistry also provides an unexpected approach to azido substituted cyclic peroxy alcohol esters. A DFT calculation indicates that Mn catalyst plays key dual roles as an efficient catalyst for the generation of azido radical and a stabilizer for peroxyl radical intermediate. Further calculation reasonably explains the proposed mechanism for the control of C-C bond cleavage or for the formation of β-azido alcohols.

β-Alkoxy sulfides are widely used as versatile building blocks in organic synthesis. Therefore, it is highly desirable to develop a convenient and efficient method for oxysulfenylation of alkenes. In this communication, an easy and efficient metal-free approach to β-alkoxy sulfides has been developed. The protocol uses readily available 1-(arylthio)pyrrolidine-2,5-diones and alcohols as the oxysulfenylating agents, chloroform as the solvent, and no ligand, additive and exclusion of air were required. Therefore, the present method provides a useful strategy for synthesis of β-alkoxy sulfides.

The first transition-metal-free carboarylation of alkynes with commercial and readily available alcohols as alkylating agents was realized in the presence of an environmentally benign calcium catalyst. Thereby, a novel protocol for the one-step synthesis of highly congested, all-carbon tetrasubstituted alkenes, as incorporated in potentially bioactive, complex dihydronaphthalene, chromene and dihydroquinoline structures, is provided. The reaction features an unprecedented, particularly wide substrate scope, good functional-group tolerance and simple experimental operation under mild reaction conditions., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted Z-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively.

A palladium-catalyzed three-component coupling of α-olefins, aryldiazonium salts, and bis(pinacolato)diboron affords direct access to chiral benzylic boronic esters. This process is rendered highly enantioselective using an unprecedented example of cooperative chiral anion phase transfer and transition-metal catalysis.

Self-assembled resorcin[4]arene hexamer catalyzes the intramolecular hydroalkoxylation of unsaturated alcohols to the corresponding cyclic ethers under mild conditions. The mode of catalysis and encapsulation-based substrate selectivity of the host efficiently mimic the basic principle of operation observed in enzymes.

A highly efficient and convenient construction of the spiro[indene-benzosultam] skeleton from propargylic alcohols has been developed. The reaction proceeded in a Lewis acid catalyzed cascade process, including the trapping of allene carbocation with sulfonamide, electrophilic cyclization, and intramolecular Friedel-Crafts alkylation. In the presence of NIS or NBS, iodo/bromo-substituted spiro[indene-benzosultam]s could be prepared in excellent yields.

The cobalt-catalyzed alkoxylation of C(sp(2) )H bonds in aromatic and olefinic carboxamides has been developed. The reaction proceeded under mild conditions in the presence of Co(OAc)2 ⋅4H2 O as the catalyst and tolerates a wide range of both alcohols and benzamide substrates, including even olefinic carboxamides. In addition, this reaction is the first example of the direct alkoxylation of alkenes through CH bond activation., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The mechanism of the redox-relay Heck reaction was investigated using deuterium-labeled substrates. Results support a pathway through a low energy palladium-alkyl intermediate that immediately precedes product formation, ruling out a tautomerization mechanism. DFT calculations of the relevant transition structures at the M06/LAN2DZ+f/6-31+G* level of theory show that the former pathway is favored by 5.8 kcal/mol. Palladium chain-walking toward the alcohol, following successive β-hydride eliminations and migratory insertions, is also supported in this study. The stereochemistry of deuterium labels is determined, lending support that the catalyst remains bound to the substrate during the relay process and that both cis- and trans-alkenes form from β-hydride elimination.

Palladium-catalyzed carbonylation of 2,4-enyne carbonates in an alcohol and under balloon pressure of CO proceeds through 1,5-substitution to yield (E)-2,3,5-trienoates. The olefin geometry of the substrate is important to control the overall stereochemistry of this alkoxycarbonylation method. The reaction proceeds through successive formation of π-allylpalladium with an R(3) group oriented syn and σ-allenyl palladium complexes.

An alkoxide-catalyzed directed diboration of alkenyl alcohols is described. This reaction occurs in a stereoselective fashion and is demonstrated with cyclic and acyclic homoallylic and bishomoallylic alcohol substrates. After oxidation, the reaction generates 1,2-diols such that the process represents a method for the stereoselective directed dihydroxylation of alkenes.

Despite recent advances of asymmetric synthesis, the preparation of enantiomerically pure (≥99% ee) compounds remains a challenge in modern organic chemistry. We report here a strategy for a highly enantioselective (≥99% ee) and catalytic synthesis of various γ- and more-remotely chiral alcohols from terminal alkenes via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)-Cu- or Pd-catalyzed cross-coupling. ZACA-in situ oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols produced both (R)- and (S)-α,ω-dioxyfunctional intermediates (3) in 80-88% ee, which were readily purified to the ≥99% ee level by lipase-catalyzed acetylation through exploitation of their high selectivity factors. These α,ω-dioxyfunctional intermediates serve as versatile synthons for the construction of various chiral compounds. Their subsequent Cu-catalyzed cross-coupling with various alkyl (primary, secondary, tertiary, cyclic) Grignard reagents and Pd-catalyzed cross-coupling with aryl and alkenyl halides proceeded smoothly with essentially complete retention of stereochemical configuration to produce a wide variety of γ-, δ-, and ε-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has been applied to the determination of the enantiomeric purities of δ- and ε-chiral primary alkanols, which sheds light on the relatively undeveloped area of determination of enantiomeric purity and/or absolute configuration of remotely chiral primary alcohols.

Various 1,4-diols are easily accessible from alkenes through iron-catalyzed aerobic hydration. The reaction system consists of a user-friendly iron phthalocyanine complex, sodium borohydride, and molecular oxygen. Furthermore, the effect of additional ligands on the iron complex was examined for a model reaction. The second hydroxy group is installed by direct C(sp(3))-H oxygenation, which is based on a [1,5] hydrogen shift process of a transient alkoxy radical that is formed by formal hydration of the olefin., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Performing catalytic enantioselective carbon-carbon bond forming reactions, especially for the synthesis of tertiary carbinols, is one of the most challenging goals in modern asymmetric synthesis. Herein, we report an efficient enantioselective catalytic approach for the 1,2-addition of arylboronic acids to trifluoromethyl ketones affording tertiary trifluoromethyl-substituted alcohols with high yields and good enantioselectivities. The reported process uses as a catalyst precursor the shelf stable sulfinamido-olefin ligand 1, "sulfolefin", obtained on a multigram scale and in one step from a sugar derived sulfinate ester.

Glowing results with less phosphorus: Tremendous progress has been made recently in asymmetric intermolecular Heck chemistry. Previously unprecedented enantioselective Heck-Matsuda reactions have been accomplished, and mixed phosphine/phosphine oxides have been shown to be superior ligands in enantioselective Mizoroki-Heck reactions. All of this was achieved with chiral ligands containing few or even no phosphorus donors (see scheme)., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG(‡) of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

The ubiquitous nature of C-H bonds in organic molecules makes them attractive as a target for rapid complexity generation, but brings with it the problem of achieving selective reactions. In developing new methodologies for C-H functionalization, alkenes are an attractive starting material because of their abundance and low cost. Here we describe the conversion of 1-alkenes into 1,4-diols. The method involves the installation of a new Si,N-type chelating auxiliary group on the alkene followed by iridium-catalysed C-H silylation of an unactivated δ-C(sp(3))-H bond to produce a silolane intermediate. Oxidation of the C-Si bonds affords a 1,4-diol. The method is demonstrated to have broad scope and good functional group compatibility by application to the selective 1,4-oxygenation of several natural products and derivatives.

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

A highly selective NHC-catalyzed synthesis of γ-butyrolactones from the fusion of enals and α-ketophosphonates has been developed. Computational modeling of competing transition states guided a rational design strategy to achieve enhanced levels of enantioselectivity with a new tailored C1-symmetric biaryl-saturated imidazolium-derived NHC catalyst.