Concise Approach to the “Higher Sugar” Core of the Nucleoside Antibiotic Hikizimycin

A highly productive synthesis of phenylthio glycoside 33 is described which constitutes a fully functional surrogate for the hikosamine core of hikizimycin 1 , a complex nucleoside antibiotic endowed with promising anthelmintic properties. The chosen approach to this undecose derivative starts from mannofuranose 7 which was one‐carbon homologated to alkyne 8 in one step on treatment with lithio (trimethylsilyl)diazomethane. Alkynyl iodide 12 derived from 8 was combined with the tartrate‐derived aldehyde 17 by a Nozaki–Hiyama–Kishi reaction that can either be performed using overstoichiometric amounts of CrCl₂ or by means of a catalytic manifold based on the turnover of a cat. CrCl₂/chlorosilane/manganese redox couple. Semi‐hydrogenation of the resulting alkyne 18 to (Z)‐olefin 19 required the use of Pd/C as the catalyst, whereas conventional Lindlar reduction was unsatisfactory. Attempted cis‐dihydroxylation of alkene 22 (formed from 19 by a Mitsunobu reaction with phthalimide) by using catalytic amounts of OsO₄ and NMO as the stoichiometric oxidant essentially failed, whereas a stoichiometric osmylation afforded the stable osmate ester 26 a as a single diastereomer. Since the use of OsO₄ in stoichiometric amounts deemed inappropriate for a total synthesis project, recourse was taken to catalytic “Blitz dihydroxylation” with RuO₄ in the presence of FeCl₂ ? 4 H₂O as co‐catalyst. Application of these conditions to alkene 30 bearing a free aldehyde function at the terminus of the “higher sugar” chain furnished pyranose 32 in good yield and excellent diastereoselectivity, which was converted into the targeted thioglycoside 33 on treatment with PhSSPh/Et₃P. It is particularly noteworthy that the conformational constraints of the acyclic substrate 30 enforce the dihydroxylation to violate Kishi's empirical rule for transformations of this type.     

锇催化烯烃双羟基化的反应原理与立体选择性

介绍了四氧化锇催化不对称烯烃双羟基化的反应原理和以N-甲基吗啉-N-氧化物（N-methylmorpholine-N-oxide,NMO）、铁氰化钾K3[Fe（CN）6] 为氧化剂时烯烃双羟基化反应的催化循环;此外,还介绍了该催化反应立体选择性的机理和一些研究进展以及催化体系中手性配体的选择。     

Stereocontrolled Synthesis of Vinyl Boronates and Vinyl Silanes via Atom‐Economical Ruthenium‐Catalyzed Alkene–Alkyne Coupling

The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru‐catalyzed alkene–alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron‐ and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross‐coupling reactions, and a Chan‐Lam‐type allyloxylation followed by a Claisen rearrangement. A sequential one‐pot alkene‐alkyne‐coupling/allylation‐sequence with an aldehyde to deliver a highly complex α‐silyl‐β‐hydroxy olefin with a handle for further functionalization was also realized.     

Platinum- and gold-catalyzed rearrangement reactions of propargyl acetates: total syntheses of (-)-alpha-cubebene, (-)-cubebol, sesquicarene and related terpenes

Propargyl acetates, in the presence of catalytic amounts of late transition-metal salts such as PtCl(2) or AuCl(3), represent synthetic equivalents of alpha-diazoketones. This notion is corroborated by a concise approach to various sesquiterpene natural products starting from readily available substrates. Specifically, (+)-carvomenthone (17) is converted into propargyl acetate (S)-26 by a sequence involving Stille cross-coupling of its kinetic enol triflate 18, regioselective hydroboration/oxidation of the resulting 1,3-diene 19, and addition of an alkynyl cerium reagent to aldehyde 21 thus obtained. Since the latter step was found to be unselective, the configuration of the reacting propargyl acetate was unambiguously set by oxidation followed by diastereoselective transfer hydrogenation by using Noyori's catalyst 25. Compound (S)-26, on treatment with PtCl(2) in toluene, converted exclusively to the tricyclic enol acetate 27, which was saponified to give norcubebone 11 in excellent overall yield. The conversion of this compound into the sesquiterpene alcohol (-)-cubebol (6) was best achieved with MeCeCl(2) as the nucleophile, whereas the formation of the parent hydrocarbon (-)-alpha-cubebene (4) was effected in excellent yield by recourse to iron-catalyzed cross coupling methodology developed in this laboratory. Since norketone 11 has previously been transformed into (-)-beta-cubebene (5) as well as (-)-4-epicubebol 8, our approach constitutes formal total syntheses of these additional natural products as well. Along similar lines, the readily available propargyl acetates 1, 33 and 47 were shown to give access to 2-carene 44, sesquicarene 39, and episesquicarene 51 in excellent overall yields. In this series, however, the cycloisomerization reaction was best achieved with catalytic amounts of AuCl(3) in 1,2-dichloroethane as the solvent. In addition to these preparative results, our data provide some insight into the mechanism of these remarkable skeletal rearrangement reactions. Transformations of this type are likely triggered by initial coordination of the alkyne unit of the substrate to the carbophilic transition-metal cation. Formal attack of the alkene moiety onto the resulting pi-complex engenders the formation of an electrophilic cyclopropyl carbene species which subsequently reacts with the adjacent acetate unit to give the final product. The alternative phasing of events, implying initial attack of the acetate (rather than the alkene moiety) onto the metal-alkyne complex, is inconsistent with the stereochemical data obtained during this total synthesis campaign.     

Chiral Diselenides in the Total Synthesis of (+)-Samin

Chiral selenium compounds are applied to stoichiometric as well as to catalytic reactions in the synthesis of substituted tetrahydrofuran derivatives: The selenium compound 1 was used in catalytic amounts for a rapid access to chiral diselenide 3. The efficient stereoselective addition to alkene 5 yields product 8 with a selenium functionality as a precursor for an intramolecular radical cyclization. In this way a short total synthesis of (+)-samin (11), a naturally occurring furofuran lignan, was achieved.     

Cobalt‐Catalyzed Annulation of Salicylaldehydes and Alkynes to Form Chromones and 4‐Chromanones

A unique cobalt(I)–diphosphine catalytic system has been identified for the coupling of salicylaldehyde (SA) and an internal alkyne affording a dehydrogenative annulation product (chromone) or a reductive annulation product (4‐chromanone) depending on the alkyne substituents. Distinct from related rhodium(I)‐ and rhodium(III)‐catalyzed reactions of SA and alkynes, these annulation reactions feature aldehyde C?H oxidative addition of SA and subsequent hydrometalation of the C=O bond of another SA molecule as common key steps. The reductive annulation to 4‐chromanones also involves the action of Zn as a stoichiometric reductant. In addition to these mechanistic features, the Co^I catalysis described herein is complementary to the Rh^I‐ and Rh^III‐catalyzed reactions of SA and internal alkynes, particularly in the context of chromone synthesis.     

Regioselective reductive coupling of alkynes and aldehydes leading to allylic alcohols

Treatment of a mixture of a terminal alkyne and an aldehyde with CrCl(2) and a catalytic amount of NiCl(2) and triphenylphosphine in the presence of water in DMF at 25 degrees C gives a 1,2-disubstituted allylic alcohol regioselectively.     

Applications of sharpless asymmetric dihydroxylation in the total synthesis of natural products

Sharpless asymmetric dihydroxylation involves the reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form an optically active vicinal diol. This reaction was primarily developed by Sharpless based on the already known racemic Upjohn dihydroxylation. The chiral diols obtained by Sharpless asymmetric dihydroxylation are important intermediates in organic synthesis. Herein, we emphasise the applications of Sharpless asymmetric dihydroxylation in the total synthesis of natural products.     

Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and alkynylsilanes: application to the synthesis of d-erythro-sphingosine

A strategy for the nickel-catalyzed reductive coupling of α-aminoaldehydes with silyl alkynes has been developed. The process proceeds with exceptional regiocontrol and diastereoselectivity. A variety of protected serinal derivatives were examined, and Garner aldehyde afforded the highest chemical yields of an easily deprotected coupling product. Use of a C-15 alkyne allowed a direct and efficient synthesis of d-erythro-sphingosine. With this silyl alkyne of interest, coupling reactions were most efficient when trace water was employed with THF as solvent. Using this procedure, d-erythro-sphingosine was prepared by a short sequence, wherein the alkene stereochemistry, C-3 stereocenter, and the C-3-C-4 carbon-carbon bond were all efficiently installed by the key nickel-catalyzed coupling process.     

Synthetic studies of the 18-membered antitumor macrolide, tedanolide. 3. Stereocontrolled synthesis of the C1-C12 part via a synthesis of the C1-C7 fragment by a mismatched but efficient sharpless dihydroxylation and its coupling with the C8-C11 fragment

The C1-C12 part (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methylpropionate (11a) via a coupling between the C1-C7 aldehyde (6) and the C8-C11 iodoalkene (7a). For a synthesis of 6, a mismatched but highly efficient Sharpless dihydroxylation of the alpha, beta-unsaturated ester (15) with AD-mix-alpha was successfully applied. Compound 7a was synthesized using hydrozirconation to the alkyne (32).     

Catalytic hydroboration of aldehydes and ketones with sodium hydride: Application to chemoselective reduction of aldehydes over ketones

Sodium hydride-promoted catalytic hydroboration of aldehydes and ketones with pinacolborane (HBpin) was examined, and 10?mol% of NaH was found to cause the HBpin to participate in hydroboration in a convenient and efficient manner at mild reaction conditions. Further chemoselective hydroboration of aldehyde over ketone functionality was also analyzed. In addition, no hydroboration was observed form ester, acyl chloride, amide, nitrile, alkene, alkyne, alkyl halide and epoxide functional groups indicate that present system (HBpin, NaH) is highly selective for aldehydes and ketones.     

Enyne metathesis-oxidation sequence for the synthesis of 2-phosphono pyrroles: proof of the "yne-then-ene" pathway

A new tandem reaction sequence has been developed for the synthesis of 2-phosphono pyrroles. The sequence consists of ring-closing enyne metathesis of a substituted aminophosphonate, containing a terminal alkyne and an internal alkene, in combination with in situ oxidation of the produced 3-pyrrolines using tetrachloroquinone. By analyzing the formation of the end and certain byproducts, taking into account the difference in reactivity of different substrates and carefully studying spectroscopic data, it was found that the reaction proceeds by means of the "yne-then-ene" pathway. During the initiation phase, a new ruthenium carbene is formed which continues the propagation cycle.     

Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a gamma-hydroxyepoxide appended to the AB spiroacetal unit

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.     

Asymmetric synthesis of the four possible fagomine isomers

The asymmetric synthesis of fagomine and its congeners 1-4 has been achieved by catalytic ring-closing metathesis (RCM). The synthesis involved the construction of the piperidene-type chiral building block 5 followed by dihydroxylation, starting from the d-serine-derived Garner aldehyde 6.     

Ruthenium-catalysed synthesis of 2- and 3-substituted quinolines from anilines and 1,3-diols

A straightforward synthesis of substituted quinolines is described by cyclocondensation of anilines with 1,3-diols. The reaction proceeds in mesitylene solution with catalytic amounts of RuCl(3)·xH(2)O, PBu(3) and MgBr(2)·OEt(2). The transformation does not require any stoichiometric additives and only produces water and dihydrogen as byproducts. Anilines containing methyl, methoxy and chloro substituents as well as naphthylamines were shown to participate in the heterocyclisation. In the 1,3-diol a substituent was allowed in the 1- or the 2-position giving rise to 2- and 3-substituted quinolines, respectively. The best results were obtained with 2-alkyl substituted 1,3-diols to afford 3-alkylquinolines. The mechanism is believed to involve dehydrogenation of the 1,3-diol to the 3-hydroxyaldehyde which eliminates water to the corresponding α,β-unsaturated aldehyde. The latter then reacts with anilines in a similar fashion as observed in the Doebner-von Miller quinoline synthesis.     

Mechanism of enyne metathesis catalyzed by Grubbs ruthenium-carbene complexes: a DFT study

The complete catalytic cycle of the reaction of alkenes and alkynes to dienes by Grubbs ruthenium carbene complexes has been modeled at the B3LYP/LACV3P**+//B3LYP/LACVP level of theory. The core structures of the substrates and the catalyst were used as models, namely, ethene, ethyne, hept-1-en-6-yne, (Me(3)P)(2)Cl(2)Ru=CH(2), and [C(2)H(4)(NMe)(2)C](Me(3)P)Cl(2)Ru=CH(2). Insight into the electronically most preferred mechanistic pathways was gained for both intermolecular as well as for intramolecular enyne metathesis. Alkene metathesis is predicted to proceed fast and reversible, while the insertion of the alkyne substrate is slower, irreversible, and kinetically regioselectivity determining. Ruthenacyclobut-2-ene structures do not exist as local minima in the catalytic cycle. Instead, vinylcarbene complexes are formed directly. The alkyne insertion step and the cycloreversion of 2-vinyl ruthenacyclobutanes feature comparable predicted overall barriers in intermolecular enyne metathesis. For intramolecular enyne metathesis, a noncyclic alkene fragment of the enyne substrate is first incorporated into the Grubbs catalyst by an alkene metathesis reaction. The subsequent insertion of the alkyne fragment then proceeds intramolecularly. Alkene association, cycloaddition, and cycloreversion to the diene product complex close the catalytic cycle. Rate enhancement by an ethene atmosphere (Mori's conditions) originates from a constantly higher overall alkene concentration that is necessary for the rate-limiting [2 + 2] cycloreversion step to the diene product complex.     

Efficient functionalization of aromatic C-H bonds catalyzed by gold(III) under mild and solvent-free conditions

A gold(III)-catalyzed carbon-carbon bond formation reaction between arenes and electron-deficient alkynes or alkenes is described. Electron-rich arenes can be efficiently functionalized with the alkyne or alkene substrates. This reaction can be run with neat reactants at ambient temperature. Under the "solventless" conditions, clean product was obtained from a reaction of equal molar amounts of arene and alkyne substrates. The mild conditions and potential tolerance to different functional groups make this method practical for arene functionalization and for constructing complicated molecules. Efficient preparation of various coumarins from aryl alkynoates was demonstrated. Preliminary mechanistic studies were performed to probe the pathway of this reaction.     

Mechanistic insight into hydrosilylation reactions catalyzed by high valent ReX (X = O, NAr, or N) complexes: the silane (Si-H) does not add across the metal-ligand multiple bond

Treatment of oxo and imido-rhenium(V) complexes Re(X)Cl3(PR3)2 (X = O, NAr, and R = Ph or Cy) (1-2) with Et3SiH affords Re(X)Cl2(H)(PR3)2 in high yields. Cycloaddition of silane across the ReX multiple bonds is not observed. Two rhenium(V) hydrides (X = O and R = Ph, 4a; X = NMes and R = Ph, 5a) have been structurally characterized by X-ray diffraction. The kinetics of the reaction of Re(O)Cl3(PPh3)2 (1a) with Et3SiH is characterized by phosphine inhibition and saturation in [Et3SiH]. Hence, formation of Re(O)Cl2(H)(PPh3)2 (4a) proceeds via a sigma-adduct followed by heterolytic cleavage of the Si-H bond and transfer of silylium (Et3Si+) to chloride. Oxo and imido complexes of rhenium(V) (1-2) as well as their nitrido analogues, Re(N)Cl2(PR3)2 (3), catalyze the hydrosilylation of PhCHO under ambient conditions, with the reactivity order imido > oxo > nitrido. The isolable oxorhenium(V) hydride 4a reacts with PhCHO to afford the alkoxide Re(O)Cl2(OCH2Ph)(PPh3)2 (6a) with kinetic dependencies that are consistent with aldehyde coordination followed by aldehyde insertion into the Re-H bond. The latter (6a) regenerates the rhenium hydride upon reaction with Et3SiH. These stoichiometric reactions furnish a possible catalytic cycle. However, quantitative kinetic analysis of the individual stoichiometric steps and their comparison to steady-state kinetics of the catalytic reaction reveal that the observed intermediates do not account for the predominant catalytic pathway. Furthermore, for Re(O)Cl2(H)(PCy3)2 and Re(NMes)Cl2(H)(PPh3)2 aldehyde insertion into the Re-H bond is not observed. Therefore, based on the kinetic dependencies under catalytic conditions, a consensus catalytic pathway is put forth in which silane is activated via sigma-adduct formation cis to the ReX bond followed by heterolytic cleavage at the electrophilic rhenium center. The findings presented here demonstrate the so-called Halpern axiom, the observation of "likely" intermediates in a catalytic cycle, generally, signals a nonproductive pathway.     

Synthesis of Pyrrolidine Derivatives by a Platinum/Brønsted Acid Relay Catalytic Cascade Reaction

A new catalytic reaction for the synthesis of pyrrolidine derivatives is presented. The method implies the coupling of N‐Boc‐protected alkynamine derivatives and appropriate alkenes or alkynes in a process catalysed by a platinum/triflic acid catalytic binary system. This reaction is believed to proceed through a cascade process implying an initial platinum‐catalysed cycloisomerization of the alkynamine derivative followed by a triflic acid promoted nucleophilic addition of the alkene or alkyne and trapping of the cationic species formed by the Boc group. Not only simple alkenes and alkynes were used in this reaction but also allyltrimethylsilane and propargyltrimethylsilane. Particularly, when allyltrimethylsilane is used as the alkene counterpart interesting bicyclic compounds containing a trimethylsilane group are obtained. However, when propargyltrimethylsilane is used in the presence of water we observed the formation of a related bicyclic compound lacking the trimethylsilane group and containing an exocyclic carbon?carbon bond.     

Catalytic "click" rotaxanes: a substoichiometric metal-template pathway to mechanically interlocked architectures

A route to mechanically interlocked architectures that requires only a catalytic quantity of template is described. The strategy utilizes the Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes. Chelating the Cu(I) to an endotopic-binding macrocycle means that the metal atom binds to the alkyne and azide in such a way that the metal-mediated bond-forming reaction occurs through the cavity of the macrocycle, forming a rotaxane. Addition of pyridine to the reaction mixture enables the Cu(I) to turn over during the reaction, permitting substoichiometric amounts of the metal to be used. The yields are very high for a rotaxane-forming reaction (up to 94% with stoichiometric Cu(I); 82% with 20 mol % of Cu(I)), and the procedure is practically simple to do (no requirement for an inert atmosphere nor dried or distilled solvents).