Catalytic asymmetric synthesis of all-carbon quaternary stereocenters

Abstract

Only a few catalytic asymmetric COC bond-forming reactions have been shown to be useful for constructing all-carbon quaternary stereocenters. This Perspective examines the current state of such methods.C arbon atoms bonded to four carbon substituents (all-carbon quaternary centers) pose a particular challenge for synthesis because creation of such centers is complicated by steric repulsion between the carbon substituents. When the four substituents differ, quaternary stereocenters become a singular challenge for achieving efficient asymmetric syntheses of chiral organic molecules (1-4). The invention of catalytic methods for asymmetric synthesis is one of the foremost recent achievements of chemistry (5), with the 2001 Nobel Prize in Chemistry recognizing William S. Knowles, Ryoji Noyori, and K. Barry Sharpless for their pioneering development of catalytic asymmetric hydrogenation and oxidation reactions. At present, many broadly useful methods for catalytic asymmetric oxidation and reduction exist; however, far fewer catalytic asymmetric methods for forming COC bonds have been invented to date (5). As disclosures in this special feature will attest, this latter area of catalytic asymmetric synthesis is a current focus of intense investigation worldwide.At present only a few catalytic asymmetric COC bond-forming reactions have been shown to be useful for constructing quaternary carbons, undoubtedly reflecting the additional steric challenge involved in forming all-carbon quaternary centers. This Perspective will examine the current state of such methods. The focus will be on reactions for which some generality has been documented, and several examples exist of reactions that proceed with enantiomeric selectivities of at least 9:1 [enantiomeric excesses (ees) Ͼ80%]. The discussion is organized by general reaction types that have proven useful, not by the more commonly used organizations that focus on one specific transformation or one family of asymmetric catalysts. It is hoped that this organization will highlight the many opportunities that exist for future discoveries in this area. The less general approach for forming allcarbon quaternary stereocenters in which a group-selective catalytic asymmetric reaction is used to desymmetrize a prochiral intermediate containing a quaternary carbon will be briefly mentioned also. No attempt to summarize this latter field will be made, as any catalytic asymmetric reaction could in principle be used in this approach. In four areas, catalytic methods for directly forming all-carbon stereocenters are most developed: Diels-Alder reactions, the combination of chiral carbon nucleophiles with carbon electrophiles, reactions of allylmetal intermediates with carbon nucleophiles, and intramolecular Heck reactions. Our discussion will begin with these reaction types. Asymmetric Diels-Alder ReactionsThe Diels-Alder reaction provides two approaches for forming quaternary stereocenters contained within the cyclohexene framework (Scheme 1). In reactions of type I, electron-rich dienes c...

Asymmetric Construction of Quaternary Carbon Stereocenter by Pd-Catalyzed Intramolecular .ALPHA.-Arylation

“…[1][2][3][4][5][6] We have been quite recently developing a novel N-heterocyclic carbene ligand 7,8) 1 based on the concept of chiral mimetic. [7][8][9][10][11][12][13] The N-heterocyclic carbene ligand 1 has been found to construct quaternary carbon streocenters with up to 65% enantioselectivity in Pd-catalyzed enantioselective intramolecular a-arylation of N-(2-bromophenyl)-N-methyl-2-arylpropanamide 2 (Chart 1).…”

Combined heterogeneous metal/organic catalysts for eco-friendly synthesis

“…Thus, we envisioned a novel highly selective ARC strategy based on combining the paradigms of heterogeneous transition metal catalysis with organocatalysis for the production of designed chiral molecules in a single purification step and under eco-friendly conditions (Scheme 1). The challenge of creating molecules with multiple and quaternary stereocenters in a highly stereoselective fashion should also be met by this tactic [24][25][26]. The underpinning of our strategy is the intrinsic ability of a heterogeneous metal catalyst to take part in several cascade sequences and cooperate with small chiral amine catalysts and substrate additives during this ARC.…”

Protecting-group directed stereospecific organocatalytic [3+2] cycloadditions: a facile access to chiral spirocyclic oxindoles

“…[8][9][10][11][12][13][14][15][16][17][18][19][20][21] The challenges associated with the stereocontrolled construction of spirocyclic oxindole core arise from introducing quaternary carbon stereocenter at C-3 of oxindole, 22,23 which is highly sterically congested. As a result, the direct catalytic enantioselective synthesis of the spirocyclic oxindole structure with two quaternary carbon chiral centers 24,25 remains a daunting challenge. Cinchona alkaloids [26][27][28][29][30][31][32][33][34][35][36][37] and their derivatives ( Figure 2) have proven to be powerful organocatalysts for various organocatalytic [38][39][40][41][42] asymmetric C-C bond formations.…”