Louis S. Hegedus

Palladium-promoted addition of amines to isolated double bonds☆

Abstract Palladium(II) complexes have been found to promote amination of terminal olefins, to give, after reduction, high yields of amines. Internal olefins may also be aminated, but the yields are moderate to low. Cyclohexene and cyclooctene react very sluggishly. In order to avoid formation of bis(amine)palladium complexes, which is a major side reaction, the temperature has to be kept low. Preliminary mechanistic studies show that three moles of amine are required per mole of palladium to ensure good yields.

Chromium carbene complexes in the synthesis of molecules of biological interest

Several new synthetic approaches to functionalized chromium aminocarbene complexes have been developed, making a wide array of complexes, including those containing optically active auxiliaries, available. Photolysis of these optically active carbene complexes in the presence of imines produces optically active p-lactams in high chemical and optical yield. Procedures for removal of the optically active auxiliary to produce the optically active free amino p- lactams have been developed. Photolysis of chromium carbene complexes was shown to produce species which react as if they were ketenes or metal-bound ketenes. Photolysis of aminocarbene complexes, synthesized from the reaction of amides with NazCr( C0)5 and trimethylsilyl chloride, in the presence of methanol produced a -amino esters in excellent yield, providing an efficient, unusual two step transformation of amides to a-amino acid derivatives. Optically active aminocarbene complexes produced optically active a-amino acids in excellent yield. Procedures to efficiently a-alkylate simple chromium (methyl)(amino)- carbene complexes have been developed. Photolysis of these homologated carbene complexes in the presence of alcohols produced h o m o alanine derivatives in excellent yield, showing the (methyl)(amino) carbene complex to be an alanine homoenolate equivalent. Optically active aminocarbene complexes were similarly homologated and photolyzed to produce optically active homoalanine derivatives. Photolysis of aminocarbene complexes in the presence of a -amino esters produced dipeptides. Preliminary results in the application of this methodology will be presented.

Palladium(II)-assisted difunctionalization of monoolefins : total synthesis of (+)-negamycin and (−)-5-epi-negamycin

(+)-Negamycin and (-)-5-epi-negamycin were synthesized by a process involving the palladium(II)-assisted alkylation of an optically active ene carbamate followed by carbonylative coupling to a trialkylvinyltin. The synthesis of (+)-negamycin was completed in 15 steps with an overs yield of 13%. The synthesis of (-)-5-epi-negamycin was completed in 12 steps with an overall yield of 20%. In preparing these compounds, a highly diastereoselective reduction of an unsaturated ketone and an efficient intramolecular Mitsunobu reaction were also carried out

Photolytic reaction of chromium and molybdenum carbene complexes with imines: synthesis of cepham, oxapenam, and oxacepham derivatives

Abstract A variety of substituted β-lactams, including a cepham analog, were synthesized by the photochemical reaction of [(methoxy)(methyl)carbene]chromium complexes with substituted imines. Oxazines and oxazolines were inert towards chromium carbene complexes. Oxazines were converted to bicyclic β-lactams by the photolytic reaction of molybdenum carbene complexes. Oxazolines were considerably less reactive and produced only low yields of β-lactam product and an equivalent amount of the corresponding oxazinone, incorporating two (MeO)(Me)C(CO) groups.

Organocatalysis in Organic Synthesis

Although examples of organocatalysissthe use of small organic molecules to catalyze organic reactionsshad been sporadically reported in the literature for decades, it was only recently realized that organocatalysis represents a fundamental concept, the development of which could provide catalysts for a wide array of important organic transformations which relied on neither transition metals nor enzymes. Early applications of organocatalysis relied on achiral compounds to promote the desired reaction, leading to achiral or racemic products.The realization that the use of enantiomerically pure compounds as catalysts could not only promote the desired reaction but also induce high enantioselectivity resulted in the dramatic expansion of the area in recent years. Organocatalysis offers many advantages for synthetic organic chemistry. In contrast to many transition metal catalysts, most organocatalysts are stable to air and water, easily handled experimentally, relatively nontoxic, and readily separated from the crude reaction mixture. Many enantiomerically pure organocatalysts are readily available from natural sources or easily prepared in a few simple steps, and often both enantiomers are available, providing ready access to both enantiomers of the desired product. Organocatalysts fall into four major classes: Lewis bases, Lewis acids, Bronsted bases, and Bronsted acids. Within each class, several modes of activation are available, and a number of organocatalysts utilize a combination of these properties to achieve the desired transformation. The 20 publications presented in this issue of JACS Select illustrate some of the many ways in which organocatalysts function. They provide a “snapshot” of this very active field for the period from mid-2008 to mid-2009, and illustrate the scope and potential of organocatalysis in synthetic organic chemistry. Activation of conjugated enones by reaction with primary amines to form iminium ions is one of the earliest modes of organocatalysis developed. Utilizing a cinchona alkaloid-derived primary amine to activate the enone, and to induce enantioselectivity as well as to suppress epoxide formation, Deng achieved the enantioselective catalytic peroxidation of conjugated enones. By increasing the temperature, the reaction could be directed to produce epoxides. Both classes of products are of biological interest, and this chemistry provides one of the very few approaches to chiral peroxides. Enamine formation by the reaction of secondary amines with aldehydes or ketones provides another mode of organocatalysis. Utilizing a proline-derived secondary amine catalyst, Jorgensen achieved the direct asymmetric catalytic synthesis of both chiral propargylic and allylic fluorides using N-fluoro-dibenzene-sulfonamide as the fluorine source and in situ conversion of the resulting R-fluoroaldehydes to the target compounds. Maruoka synthesized (S)-2-tritylpyrrolidine as a catalyst for the direct asymmetric R-benzoyloxylation of aldehydes with benzoyl peroxide as the electrophile, when existing proline-derived catalysts proved ineffective. Both sets of compounds are important building blocks for organic synthesis, while fluorinated compounds are of substantial interest to medicinal chemists. A third mode of organocatalysis involves asymmetric phase-transfer catalysis. The catalysts are usually chiral quaternary ammonium salts, with those derived from cinchona alkaloids being among the most utilized. Hydrogen bonding is thought to play a key role in the process. A very diverse range of organic reactions can be effected under phase-transfer catalysis, and the process serves as an important synthetic method. Dixon developed an adamantyl-containing cinchona-based catalyst for the enantioand diastereoselective ring-opening of aziridines by cyclic -ketoesters to produce γ-butyric acid derivatives. Fini and Bernardi used a quininederived phase-transfer catalyst to promote the asymmetric [3+2] cycloaddition of nitrones to conjugated esters, producing isoxazolidines with three contiguous stereocenters. These heterocycles can serve as precursors to useful compounds such as aminoalcohols, amino acids,

3.1 – Heteroatom Nucleophiles with Metal-activated Alkenes and Alkynes

Electron-rich, unsaturated hydrocarbons, which are normally resistant to nucleophilic attack, become generally reactive towards nucleophiles upon complexation to an electrophilic transition metal such as palladium(II), platinum(II) or iron(II). Complexation also directs the regio- and stereo-chemistry of the nucleophilic attack, the result of which is a new organometallic complex, which can often be used to promote additional functionalization of the original substrate. Synthetically useful examples of such processes are presented in the following sections.

Palladium-catalyzed synthesis of heterocycles

Abstract Ortho -allylanilines were cyclized to indoles using a palladium(II)-catalyzed intramolecular amination of the olefinic side chain. A general approach to diaminobenzoquinones was developed, and preliminary studies of a palladium(II)-catalyzed approach to the mitomycins were initiated. o -Bromo- N -allylanilines were cyclized to indoles or quinolines using palladium(O) catalysis. Non-aromatic olefinic amines were converted to their sulfonamides and cyclized to sulfonated cyclic enamines using palladium(II) catalysts. A new synthesis of β-lactams from imines and chromium carbene complexes was developed.

Synthesis of optically active amino azapenams by the photolytic reaction of chromium aminocarbene complexes with N-protected imidazolines

Abstract Photolysis of optically active aminocarbene chromium complexes with N-protected imidazolines produced α-amino-N-protected azapenams in good yield and with high diastereoselectivity. Removal of the protecting group resulted in cleaving of the β-lactam to give N-acylimidazolines.

Syntheses and reactions of optically active α-aminoallenylstannanes and α-aminopropargylboranes

An efficient synthesis of α-aminoallenylstannane from propargyloxazolidinone has been developed. It undergoes reaction with aldehydes to give homopropargylic alcohols with high syn selectivity. Epoxides undergo a similar reaction preceded by rearrangement to the aldehyde. These alcohols were used in the synthesis of β-amino acids, azasugars, and deoxyaminohexoses. Imines underwent reaction with this stannane to give 1,2-diamines. The related propargylborane reacts with aldehydes to produce allenyl carbinols. The Co2(CO)6 complexes of propargyloxazolidinones were developed as an α-aminopropargyl cation equivalent.

Carbon Nucleophiles with Alkenes and Alkynes

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions are strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles are studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals.