Efficient asymmetric Suzuki-Miyaura coupling reactions are employed for the first time in total syntheses of chiral biaryl natural products korupensamine A and B in combination with an effective diastereoselective hydrogenation, allowing ultimately a concise and stereoselective synthesis of michellamine B. Chiral monophosphorus ligands L1-3 are effective for the syntheses of a series of functionalized chiral biaryls by asymmetric Suzuki-Miyaura coupling reactions in excellent yields and enantioselectivities (up to 99% ee). The presence of a polar-π interaction between the highly polarized BOP group and the extended π system of arylboronic acid coupling partner is believed to be important for the high enantioselectivity.

Despite the signficant advances in asymmetric hydrogenation, the development of novel and efficient chiral phosphorus ligands to solve new synthetic challenges continues to an important goal. [1] C 2 -Symmetric chiral bisphosphorus ligands such BINAP, [2] DuPhos, [3] and TangPhos [4] are among the most versatile and important ligands for asymmetric hydrogenation, yet they are not universal. To expand their synthetic utilities, one common strategy is to develop structurally similar ligands, such as Tol-BINAP, Xyl-BINAP, Et-DuPhos, or iPr-DuPhos by increasing the size of the substituents on the phosphorus centers (Figure 1 a). Such modifications lead to the design of ligands with deeper chiral pockets mainly owing to the increased bulk of the R groups, which protrude slightly forward to the substrate coordination. In this study we adopt a new strategy to design a ligand with a deep chiral pocket by installing R groups that protrude directly forward to the substrate coordination site. There are two advantages of this strategy: 1) The R groups that protrude directly forward to the substrate coordination site can lead to a dramatic conformational variation of the chiral pocket; 2) the R groups are in close proximity to the metal center and the substrate, thereby providing a well-defined and deep chiral pocket. We herein report the development of WingPhos (L5) by using this strategy.Chiral b-arylamines exist in numerous biologically interesting natural products and therapeutic agents. For examples, such moieties commonly exist in a series of naphthylisoquinoline alkaloids such as michellamine B and korupensamine A (Scheme 1). [5] They also serve as pivotal structural units for many active pharmaceutical ingredients such as 3,4-methylenedioxyamphetamine (MDA), [6a] tamsulosin, [6b] selegiline, [6c] arformoterol, [6d] rotigotine, [6e] and silodosin. [6f] Development of efficient asymmetric synthetic methods of chiral b-arylamines has thus become a subject of significant interest. [7] However, the asymmetric hydrogenation of b-aryl enamides to prepare chiral b-arylamines remains underdeveloped. Zhang, Lei, and co-workers reported high enantioselectivities on the asymmetric hydrogenation of (Z)-b-aryl enamides by using a Rh-TangPhos catalyst. [8] Nevertheless, low ee values were observed with thermodynamically more stable sub-Figure 1. Design of novel chiral bisphosphorus ligand L5 (WingPhos) with a deep chiral pocket (9-An = 9-anthracenyl). Scheme 1. Selected natural products and therapeutic agents containing chiral b-arylamines.

The enantioselective formation of quaternary carbon stereocenters in complex natural product synthesis in the latest six years is reviewed, with particular emphasis on the analysis of the stereochemical model of each enantioselective transformation.

Delavatine A (1) is a structurally unusual isoquinoline alkaloid isolated from Incarvillea delavayi. The first and gram-scale total synthesis of 1 was accomplished in 13 steps (the longest linear sequence) from commercially available starting materials. We exploited an isoquinoline construction strategy and developed two reactions, namely Rh-catalyzed asymmetric hydrogenation of indene-type tetrasubstituted olefins and kinetic resolution of β-alkyl phenylethylamine derivatives through Pd-catalyzed triflamide-directed C-H olefination. The substrate scope of the first reaction covered unfunctionalized olefins and those containing polar functionalities such as sulfonamides. The kinetic resolution provided a collection of enantioenriched indane- and tetralin-based triflamides, including those bearing quaternary chiral centers. The selectivity factor (s) exceeded 100 for a number of substrates. These reactions enabled two different yet related approaches to a key intermediate 28 in excellent enantiopurity. In the synthesis, the triflamide served as not only an effective directing group for C-H bond activation but also a versatile functional group for further elaborations. The relative and absolute configurations of delavatine A were unambiguously assigned by the syntheses of the natural product and its three stereoisomers. Their cytotoxicity against a series of cancer cell lines was evaluated.

Pyrrolidines and piperidines are important building blocks in organic synthesis. Numerous methods exist for constructing substituted pyrrolidines and piperidines. However, efficient syntheses of pyrrolidines and piperidines bearing chiral tertiary alcohols are limited. Here we report an efficient enantioselective nickel-catalyzed intramolecular reductive cyclization of Nalkynones. A P-chiral bisphosphorus ligand DI-BIDIME is designed and applied in the synthesis of tertiary allylic siloxanes bearing pyrrolidine and piperidine rings in high yields and excellent enantioselectivities, with triethylsilane as reducing reagent. The highest turn over number achieved is 1000 (0.1 mol% catalyst loading) with > 99:1 er. This reaction provides a practical way to synthesize pyrrolidine and piperidine derivatives with chiral tertiary alcohols from easily accessible starting materials under mild conditions. The products can be scaled up and transformed to various useful chiral intermediates. The P-chiral bisphosphorus ligand developed in this study represents one of the few ligands for highly enantioselective cyclization of alkynones.

A phase transfer catalyzed asymmetric alkylation of anthrones with cyclic allylic bromides using quinidine- or quinine-derived catalysts is described. Utilizing mild basic conditions and as low as 0.5 mol % catalyst loading, and achieving up to >99:1 dr selectivity, this asymmetric reaction was successfully applied to produce enantioselectively (−)- and (+)-viridicatumtoxins B, and thus allowed assignment of the absolute configuration of this naturally occurring antibiotic. While the developed asymmetric synthesis of C10 substituted anthrones is anticipated to find wider applications in organic synthesis, its immediate application to the construction of a variety of designed enantiopure analogues of viridicatumtoxin B led to the discovery of highly potent, yet simpler analogues of the molecule. These studies are expected to facilitate drug discovery and development efforts toward new antibacterial agents.

A highly regioselective hydroaminomethylation of terminal olefins catalyzed by Rh complexes with 2, 2', 6, 6'-tetrakis ((diphenylphosphino)methyl)-1, 1'-biphenyl (Tetrabi) ligand has been developed. Up to 99 % amine selectivity, 168 linear/branched amine product ratio (n/i), and 97.4 % linear amine yield has been obtained at a substrate/rhodium precursor ratio (S/Rh) of 1000 with this methodology. The turnover number was achieved 6930 at 10,000 S/Rh ratio, and the n/i can reach up to >525. Several different olefins and secondary amines have been applied successfully with high chemoselectivity (99 %), yield (>98 %), and regioselectivity (>120).

A new class of substituted tetraphosphine ligands has been applied in the rhodium-catalyzed regioselective isomerization-hydroformylation of internal olefins. The rhodium/tetraphosphine ligand system is highly effective for the isomerization and hydroformylation of 2-alkenes to form linear aldehydes. Greater than 95% linear selectivity and up to 94% yield of the total aldehydes were obtained for 2-pentene, 2-hexene and 2-octene. The catalyst system also showed high to moderate linear selectivity for the isomerization and hydroformylation of 3-hexene, 3-octene and 4-octene but with slow reaction rates.