Volume 74, Issue 1

On the basis of fundamental studies on the carbon­oxygen bond cleavage of various carboxylic acid derivatives, novel, atom-efficient, and environmentally benign catalytic processes to convert them into acids, aldehydes, and ketones have been developed.

Ruthenium-catalyzed olefin cross-metathesis tolerates a wide range of functional groups, including phosphine-boranes, sulfides, amines, phenols, and oxazolines. The high functional group tolerance allows for the use of an olefin as a linchpin for the synthesis of a variety of bi-, tri-, and tetradentate chiral ligands with a high degree of functional group diversity.

Highly functionalized Grignard-reagents can be easily obtained by an iodine­magnesim exchange reaction and further reacted with various electrophiles. Via a B­Zn exchange reaction, a formal Michael addition with umpolung of the reactivity can be achieved. Chiral phosphine ligands can be easily synthesized by a 2.3 sigmatropic rearrangement and used successfully in asymmetric synthesis.

Ruthenium, rhodium, iridium, and rhenium hydride complexes are highly useful redox Lewis acid and base catalysts. Various substrates bearing hetero atoms are activated by these catalysts and undergo reactions with either nucleophiles or electrophiles under neutral conditions. These types of catalytic reactions are described together with their application to the preparation of various biologically active compounds.

Studies in our laboratory are directed at the advancement of synthesis, biology, and medicine. This lecture will focus on new transition metal-catalyzed reactions that have been inspired by biologically potent targets such as phorbol and Taxol® and by the more general interest in producing syntheses that are concise, efficient, cost- and resource-effective, environmentally benign, quick, and simple to conductin essence, ideal. A special emphasis in our program is placed on new transition metal-catalyzed reactions that, in the absence of catalyst, would be forbidden or difficult to achieve. We have thus far reported the first examples of intramolecular metal-catalyzed [4+2], [5+2], and [4+4] cycloadditions, reactions that produce 6-, 7-, and 8-membered rings, respectively. Recent advances in our [5+2] cycloaddition studies will be presented, including new catalysts for relative and absolute stereochemical control. We will also describe recyclable catalysts that can be used in water, thereby minimizing cost and environmental concerns about solvent waste streams. New multicomponent reactions will also be presented. Finally, we will report a new [6+2] cycloaddition that produces an 8-membered ring.

An overview is provided of our work on tin hydride-catalyzed processes, palladium-catalyzed coupling reactions, and asymmetric catalysis with "planar-chiral" heterocycles.

Copper-catalyzed reactions include the enantioselective conjugate addition and the SN2¢ substitution. We describe the genesis of these reactions, the choice of the primary organometallic reagent, and our studies on finding new Michael acceptors and new ligands. We also report on the use of the zinc enolate generated upon conjugate addition.

The use of air- and water-stable organoboron compounds for C­C bond-forming reactions are reported. These studies include the Lewis acid-promoted additions of boronic esters to N-acyliminium ions and allyl and crotyltrifluoroborate salts to aldehydes. Aryl and alkenyltrifluoroborate salts will add to aldehydes under the influence of rhodium catalysis or in the presence of zinc metal. These salts also participate in palladium-catalyzed Suzuki­Miyaura and other cross-coupling reactions. Finally, a new type of N-heterocyclic carbene ligand is reported and used for Pd-catalyzed Suzuki­Miyaura couplings.

Tricarbonylchromium complexes of benzocyclobutenone, benzocyclobutenedione, and 1,3-indandione are readily prepared by hydrolysis of the complexes of the corresponding acetals. Reduction of the benzocyclobutenone complex gives rise to an oxy-anion-driven ring opening to the corresponding ortho-quinodimethane intermediate, which can be trapped with dienophiles. Addition of 1-ethoxy-1-lithioethene allows a stereoselective ring expansion followed by an anionic ketol rearrangement with complete diastereoselectivity. Addition of 1-lithio-1-methoxyallene gives rise to a rare anionic 1-vinylcyclobutenol-cyclohexadienol rearrangement. Diaddition of alkenylmetal reagents at both keto groups in benzoyclobutenedione complexes causes dianionic oxy-Cope rearrangements to occur at ­78 °C, which are followed by diastereoselective intramolecular aldol additions. In some cases, a completely regioselective mono hydrolysis of di(enolates) was observed. Dianionic oxy-Cope rearrangements can also be realized with unstrained benzil derivatives giving 1,6-hexanediones and the corresponding aldol adducts. The 1,2,3-indantrione complex is obtained by oxidation of the 1,3-indandione complex with dimethyldioxirane in good yield and reacts with its central ketone group in hetero Diels­Alder cycloadditions.

A new methodology is described, consisting of the use of molecular pools in palladium-catalyzed sequential processes occurring under mild conditions with high selectivity. These reactions involve palladacycle formation from aryl iodide, palladium, and norbornene, the latter behaving as a second catalyst that is first incorporated into the metallacycle and expelled at the end of the process. Selective alkylation or arylation of the arene nucleus occurring by oxidative addition/reductive elimination of palladacycles are coupled, after norbornene expulsion, with C­H or C­C bond-forming reactions such as hydrogenolysis, olefin insertion, arylboronic coupling, etc. The variety of possible combinations offers a powerful tool for the selective synthesis of unusual and not readily accessible aromatics.

In this article, new metal-mediated cyclization and reductive coupling reactions of bicyclic olefins with alkynes are described. Oxabicyclic alkenes undergo cyclization with alkyl propiolates at 80 C catalyzed by nickel complexes to give benzocoumarin derivatives in high yields. The reaction of bicyclic alkenes (oxa- and azacyclic alkenes) with alkyl propiolates at room temperature in the presence of the same nickel complex gave 1,2-dihydro-napthelene derivatives in good-to-excellent yields. This reductive coupling reaction proceeds under very mild conditions in complete regio- and stereoselective fashion. A mechanism to account for the coumarin formation and the reductive coupling is proposed.

CODRu(h3methylallyl)2 is a versatile starting material for the preparation of a wide range of chiral bisphosphines ruthenium(II) complexes: (P*P)Ru(h3methylallyl)2 2, Ru[X4(P*P)2] 3, and cationic monohydride ruthenium complex 4. A facile synthesis of new C2 electron-rich chiral phosphines, bis(phosphetano)benzene 8 and 1,1¢bis(phosphetano)ferrocene 10 is presented. Dynamic kinetic resolution was used for efficient syntheses of key components of the hexahydroazepane core 16 of balanol and of optically pure Boc-(2S,3R,3S)-iso-dolaproïne 19. Catalyst 4 was used in asymmetric hydrogenation of 22 to give (+)-cis-methyl dihydrojasmonate in high enantioselectivity.

Cocyclization of alkynes, alkenes, and carbon monoxide by transition metals (known as Pauson­Khand reaction when dicobalt octacarbonyl complexes are used) has been accepted as one of the most powerful tools in the synthesis of cyclopentenones. Despite significant progress in the various aspects of the reaction, we still needed new catalysts to expand the scope of the reaction further. We found rhodium (I) catalysts, e.g., RhCl(PPh3)3, trans-RhCl(CO)(PPh3)2, RhCl-(CO)(dppe), and trans-[RhCl(CO)(dppp)]2, were also effective for this transformation. The scope and the efficiencies of the reaction could be tuned and expanded by the choice of catalysts. For example, we were able to devise an enantioselective PK-type reaction and a tandem strategy employing two catalysts in one pot. These results will be presented.

The consecutive oxidative polycyclization reaction with rhenium(VII) oxides represents a highly stereoselective synthetic tool by which polyenes that contain a bis-homoallylic alcohol can be transformed into poly-THF products in a single step. On the basis of a detailed study with model substrates, a set of rules is proposed to predict product configurations in the polycyclization reactions with trifluoroacetylperrhenate. This methodology is exceptionally useful for the synthesis of polyoxygenated carbon skeletons that contain many stereogenic centers, and for the Annonaceous acetogenins in particular. Many of these potent antitumor agents, including solamin, reticulatacin, asimicin, bullatacin, trilobin, trilobacin, squamotacin, rolliniastatin, uvaricin, rollidecins C and D, mucocin, goniocin, and cyclogoniodenin T, as well as chemical libraries of non-natural analogs, were synthesized using the oxidative polycyclization reaction in combination with the Sharpless AD and AE reactions.

Selenides, selenoxides, osmium tetroxide, and potassium osmate dihydrate are in equilibrium in aqueous tert-butanol containing potassium carbonate. We took advantage of this feature to withdraw the equilibrium in each of the two directions to produce allylalcohols from allylselenides and diols from olefins. The latter reaction performed in the presence of catalytic amounts of Cinchona alkaloids and osmium tetroxide allows the enantioselective dihydroxylation of C,C double bonds.

Given the stability of the bond between a mercaptide ligand and various redox-active metals, it is of interest that Nature has evolved significant metalloenzymatic processes that involve key interactions of sulfur-containing functionalities with metals such as Ni, Co, Cu, and Fe. From a chemical perspective, it is striking that these metals can function as robust biocatalysts in vivo, even though they are often "poisoned" as catalysts in vitro through formation of refractory metal thiolates. Insight into the nature of this chemical discrepancy is under study in order to open new procedures in synthetic organic and organometallic chemistry.

The chemistry of bidentate Lewis acids belongs to an unexplored field of science, and so far has been only poorly studied. This paper illustrates the design of several bidentate Al and Ti Lewis acids, and their successful application to selective organic synthesis, particularly to asymmetric synthesis. For example, a new, chiral bidentate Ti(IV) complex is successfully designed by adding commercially available Ti(OPri)4 and (S)-binaphthol sequentially to 2,2'-bis(tritylamino)-4,4'-dichlorobenzophenone in CH2Cl2, and can be utilized for simultaneous coordination to aldehyde carbonyls, thereby allowing the precise enantioface discrimination of such carbonyls for a new catalytic, practical enantioselective allylation of aldehydes with allyltributyltin. This chiral bidentate Ti(IV) catalyst exhibits uniformly high asymmetric induction as well as high chemical yields for various aldehydes. The present enantioselective allylation is highly chemoselective in the presence of other carbonyl moieties.

Substrates that possess an a,b-unsaturated carbonyl tethered to an alkyne have been utilized in a variety of nickel-catalyzed processes. Depending on ligand structure, reagent structure, reaction conditions, and workup conditions, several different monocyclic and bicyclic ring systems may be accessed from a common substrate. Evidence for a nickel metallacycle as a common intermediate is provided.

Two organometallic themes of current interest are presented. The scope and generality of the reductive deoxygenation of carbonyl compounds to organozinc carbenoids using zinc in combination with a silicon electrophile is discussed. Alkoxycyclopropanation can be achieved using orthoformates as substrates. Preliminary observations on the development of a rhodium-catalyzed tandem hydrosilylation­intramolecular aldol sequence are discussed.

Electrophilic amination of Grignard reagents is accomplished by using O-sulfonyl-oximes of benzophenone derivatives. In the presence of a catalytic amount of CuCN, O-sulfonyloxime of 4,4¢-bis(trifluoromethyl)benzophenone reacts with alkyl Grignard reagents in tetrahydrofuran (THF) and hexamethylphosphoramide (HMPA), yielding primary alkyl-amines by successive hydrolysis of the resulting N-alkylimines. Arylamines are also prepared as well as alkylamines by treating O-sulfonyloxime of 3,3¢,5,5¢-tetrakis(trifluoromethyl)benzophenone in toluene-ether with Grignard reagents. Various cyclic imines are synthesized by palladium-catalyzed cyclization of olefinic oxime derivatives. That is, the reaction of O-pentafluorobenzoyloximes of olefinic ketones with a catalytic amount of Pd(PPh3)4 and triethylamine in dimethylformamide (DMF) affords nitrogen-containing heterocycles, such as pyrroles, pyridines, isoquinolines, spiro-imines, and aza-azulenes. This reaction proceeds via the initial formation of alkylideneaminopalladium species generated by oxidative addition of oximes to Pd(0), and the successive intramolecular Heck-type amination occurs on the olefinic moiety.

The discovery, methodological developments, including those for separation­purification of chiral flexible primary alcohols, and their applications to the syntheses of some natural products of the titled reaction are discussed.

Recent development in the transition metal-catalyzed cyclization reactions for organic syntheses in the author's laboratories is summarized, which includes (i) novel silylcarbocyclizations (SiCaCs) and carbonylative carbotricyclizations, (ii) intramolecular silylformylations and desymmerization of siloxydiynes by sequential double silylformylation, (iii) efficient total synthesis of (+)-prosopinine, (iv) enantioselective desymmetrization of aminodienes, and (iv) new and efficient routes to 1-azabicyclo[x.y.0]alkane amino acids. All these processes are catalyzed by Rh or Rh­Co complexes, and useful for rapid and efficient construction of a variety of heterocyclic and carbocyclic compounds. Mechanisms of these new carbocyclization and cyclohydrocarbonylation reactions are also discussed.

Semiempirical and density functional theory (DFT) calculations have been performed on the key steps of the commonly accepted mechanism of the Pauson­Khand reaction (PKR). In this context, the high reactivity of ynamine complexes in the cycloaddition process has been rationalized on the basis of an anomerically assisted dissociation of CO. Moreover, an explanation has been provided for the correlation between olefin strain and reactivity in the PKR. Inspired by these results, new selective syntheses of cyclopentanones and phenols based on PKR with cyclopropene have been developed. On the other hand, the theoretical analysis of phosphine-substituted dicobalt carbonyl complexes of alkynes has helped in the development of efficient chelating (P,N) and bridging (P,S) ligands for the stereochemical control of the reaction and in the understanding of their action modes.

n-Butyllithium smoothly deprotonates alkoxyallenes at C-1. The generated lithiated species reacts with a variety of electrophiles furnishing after cyclization functionalized furan, pyrrole, or 1,2-oxazine derivatives. The formation of new C­C bonds often occurs with high stereoselectivities, which are exploited for efficient and selective syntheses of natural products or other compounds of interest.

Heteroatom-COX species where the heteroatom is Cl, S, or Sn and X is alkoxy, amino, or alkoxycarbonyl group were found to add to the triple bond of alkynes regio- and stereoselectively in the presence of Rh, Pd, or Ni catalyst. Scope and limitation of these synthetic reactions were disclosed. Mechanistic study revealed that oxidative addition of these heteroatom-COX bonds readily took place and the resulting adducts were isolable and characterized by X-ray diffraction analysis. Synthetic applications of the catalytic reactions were also demonstrated.