Recent developments in asymmetric catalytic addition to CN bonds

The catalytic asymmetric addition reactions of organometallic reagents to CdN double bonds of imines are fundamentally important processes, which provide convenient and versatile routes to optically active amines bearing a stereogenic center at the R-position. Optically active R-branched amines are important chiral building blocks, and are abundantly present in biologically active compounds, such as methoxyphenamine (a 2-adrenergic antagonist for treatment of asthma), rivastigmine (an AcCh esterase inhibitor for treatment of Alzheimer’s disease), tamsulosin (a selective R1-adrenergic antagonist to improve urinary trouble due to prostatic hyperplasia), and repaglinide (a blocker of ATP-dependent K channels in cells used as a hypoglycemic agent) (Figure 1). Asymmetric addition to CdN double bonds has been achieved based on the use of a chiral auxiliaries or chiral ligands. In 1982, Takahashi and co-workers reported the pioneering work of a chiral auxiliary-controlled asymmetric addition of organolithium reagents to imines 1 derived from aldehydes and valinol or phenylglycinol (Scheme 1). The chiral auxiliary strategy is still an important technology from a practical point of view because separation of the diastereomeric products prior to cleavage of the chiral auxiliary provides enantiomerically pure products. In the past two decades, the asymmetric additions of organometallic reagents to the CdN double bonds of imines in the presence of a stoichiometric or catalytic amount of a chiral ligand have been developed as a new technology for the synthesis of optically active amines, including alkaloids. The ligandinduced enantioselective synthesis has the potential for direct recovery and reuse of the unchanged chiral ligands. In 1990, Tomioka and co-workers reported the first chiral ligandcontrolled asymmetric addition reaction of organometallic compounds to CdN double bonds of imines with organolithium reagents activated by a chiral amino ether ligand 5 (Scheme 2). Even with 5 mol % of ligand 5, enantiomerically enriched amine 6 was produced, though with moderate ee, opening up the door to catalytic asymmetric addition reactions of organometallic reagents to a CdN double bond of an imine. Denmark and co-workers also showed the excellent ability of asymmetric induction of (-)-sparteine and bisoxazoline ligands and the catalytic use of these ligands for addition of organolithium reagents to imines (Scheme 3). In 1992, Soai and co-workers reported the first catalytic asymmetric addition reaction of a dialkylzinc reagent to a CdN double bond. In the presence of chiral amino alcohol 11, addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines proceeded with high enantioselectivity (Scheme 4). Surprisingly good enantioselectivity was observed even with 10 mol % of the amino alcohol, although the chemical yield was not satisfactory. Since these early examples, considerable energetic approaches toward the catalytic asymmetric addition of organometallic reagents to CdN double bonds of imines have appeared. Among these, chiral π-allylpalladium-catalyzed allylation with allylstannane or allylsilane, and rhodiumMOP-based phosphine-catalyzed arylation with arylstannanes showed impressive early success. A key concept is catalytic generation of reactive organometal-chiral ligand complexes from corresponding less reactive organometallic reagents in situ. Excellent feature articles have been published on this exciting topic. However, in great contrast to the chiral amino alcohol catalyzed asymmetric alkylation of aldehydes with organozinc reagents, which has become a very effective and general method, the catalytic asymmetric * To whom correspondence should be addressed. Tel: 81-(0)75-753-4553. Fax: 81-(0)75-753-4604. E-mail: tomioka@pharm.kyoto-u.ac.jp. Chem. Rev. 2008, 108, 2874–2886 2874

Copper-catalyzed asymmetric alkylation of imines with dialkylzinc and related reactions.

The formation of C–C bonds via catalytic hydrogenation and transfer hydrogenation enables carbonyl and imine addition in the absence of stoichiometric organometallic reagents. In this review, iridium-catalyzed C–C bond-forming hydrogenations and transfer hydrogenations are surveyed. These processes encompass selective, atom-economic methods for the vinylation and allylation of carbonyl compounds and imines. Notably, under transfer hydrogenation conditions, alcohol dehydrogenation drives reductive generation of organoiridium nucleophiles, enabling carbonyl addition from the aldehyde or alcohol oxidation level. In the latter case, hydrogen exchange between alcohols and π-unsaturated reactants generates electrophile–nucleophile pairs en route to products of hydro-hydroxyalkylation, representing a direct method for the functionalization of carbinol C–H bonds.

/pdf/formation-of-c-c-bonds-via-iridium-catalyzed-hydrogenation-bg7hvo5b2c.pdf

Formation of C–C Bonds via Iridium-Catalyzed Hydrogenation and Transfer Hydrogenation

Formation of C—C Bonds via Iridium-Catalyzed Hydrogenation and Transfer Hydrogenation

Ring-rearrangement metathesis (RRM) refers to the combination of several metathesis transformations into a domino process, in which an endocyclic double bond of a cycloolefin reacts with an exocyclic alkene. RRM has proven to be a powerful method for the rapid construction of complex structures. The extension of the basic ring-opening-ring-closing metathesis process by further metathesis steps as well as an examination of the driving forces, limits, scope, recent advantages, and future perspectives of these domino sequences is presented with various examples, thus reflecting the high efficiency and utility of RRM in organic synthesis.

Ring-rearrangement metathesis.

Catalytic Asymmetric Addition of Dialkylzinc Reagents to α-Aldiminoesters

Ring-rearrangement metathesis of bicyclic amino acid derivatives

The first catalytic, enantioselective addition of organozinc reagents to α-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.

/pdf/catalytic-asymmetric-addition-of-dialkylzinc-reagents-to-a-1onqvaaqgq.pdf

Catalytic Asymmetric Addition of Dialkylzinc Reagents to α‐Aldiminoesters.

This chapter focuses on the application of ruthenium-catalyzed olefin metathesis to the synthesis of piperidine and pyrrolidine containing compounds. Olefin metathesis has proved to be a powerful synthetic tool in organic synthesis. The advent of well-defined metal carbene complexes with remarkable functional group tolerance has rendered metathesis as an efficient route to the synthesis of new C–C bonds. Aside from polymerization reactions, olefin metathesis can be classified into three categories: ring-closing metathesis (RCM), ring-opening metathesis (ROM), and cross metathesis (CM). In classical organic synthesis, the individual bonds in the target molecule are usually formed step by step. Starting from relatively simple starting compounds, the structural complexity in the molecule slowly increases in the course of the synthesis. Domino, or tandem, reactions are processes that involve at least two transformations in one step, in which the subsequent reaction always occurs at the functionality formed in the previous step. These transformations can be either bond formation or bond cleavage. For example, linking several metathesis reactions allows for the rapid construction of complex structures from simple precursors in only one pot. Domino metathesis reactions of this type can be referred to as “ring rearrangement metathesis” (RRM).

Chapter 12 - Ring Rearrangement Metathesis (RRM) – A New Concept in Piperidine and Pyrrolidine Synthesis

Ring-Rearrangement Metathesis of Bicyclic Amino Acid Derivatives.

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