Enantioselective total syntheses of ropivacaine and its analogues

Organic & Biomolecular Chemistry, 2007

This work reports the synthesis of new axially chiral bridged 2,2 -bipyridines 1 and pyridylmonooxazolines (pymox) 2. The potential of these new axially chiral N,N-ligands was evaluated in asymmetric catalytic cyclopropanation of styrene derivatives 22a-c with diazoesters 21a,b. While 2,2 -bipyridines 1a-c afforded the corresponding cyclopropanes 23a-f in up to 65% ee, pymoxs 2a-e gave somewhat lower enantioselectivities (up to 53% ee). Both classes of ligands produced trans-cyclopropanes 23a-f as the major isomer, although with modest diasteroselectivities (56 : 44 to 78 : 22). A structure-stereoselectivity relationship study of ligands 1 and 2 identified the chiral biaryl axis as being mostly responsible for the enantioselective performances of these ligands.

Angewandte Chemie International Edition, 2007

The remarkable influence of catalytic olefin metathesis is due to the availability of Mo-and Ru-based catalysts. One notable (and fortunate) aspect of these two classes of initiating alkylidenes and carbenes is that they are complementary in regards to functional-group tolerance. Unlike Mo alkylidenes, Ru carbenes promote transformations of substrates that bear a hydroxyl group; Mo-based systems, on the other hand, often retain their high activity in the presence of unhindered tertiary amines. Herein, we report a method for catalytic asymmetric ring-opening/cross-metathesis (AROM/CM) of unsaturated azabicycles; functionalized piperidines are formed in up to 98 % ee and with greater than 98 % E selectivity. With a few exceptions, high reactivity is observed only with Mo complexes. The present studies put forth the first catalytic AROM/CM protocol for enantioselective synthesis of N-containing heterocycles. During the past several years, we have introduced chiral Ru- (e.g., 1-2; Scheme 1) and Mo-based (e.g., 3-6) complexes that promote asymmetric ring-closing metathesis (ARCM) and ring-opening metathesis (AROM). In connection with catalytic AROM/CM, the majority of studies have involved reactions of meso norbornenes that deliver enantiomerically enriched cyclopentanes. One of the more noteworthy applications of these chiral complexes, however, relates to enantioselective synthesis of piperidines, components of numerous biologically active compounds. We have reported a catalytic AROM/CM protocol that yields functionalized pyrans in high enantiomeric purity (up to 98 % ee; > 98 % E selectivity in all cases). [8c] To promote enantioselective reactions of the oxabicycles, we utilized Ru-based chiral complexes (1-2), which, however, often do not promote reactions of N-containing substrates (see below for examples).

Chirality, 2005

Dedicated to Professor Volker Schurig on the occasion of his 65th birthday.

Angewandte Chemie International Edition, 2011

Vinylcyclopropanes (VCP) are important synthons in organic synthesis because of the presence of a highly strained ring system in conjugation with a carbon-carbon double bond, thus enabling these compounds to participate in a wide range of reactions. This structural motif is found in numerous naturally occurring optically active compounds that are important intermediates in the biosynthesis of terpenes. Furthermore, these compounds are prone to pyrolysis, electrophilic ring opening, and acid-catalyzed rearrangement, thus leading to structurally interesting compounds. Herein, a one-pot synthesis of enantiomerically pure bicyclic amidines from bicyclic vinylcyclopropanes is reported (Scheme 1). Amidines have attracted considerable interest owing to their diverse applications in the fields of chemistry and biology. Chiral amidine scaffolds are efficient organocatalysts and excellent ligands for transition-metal-based asymmetric catalysis, thus providing good enantioselectivity. [5] However, only a few methods are available for the synthesis of amidines with a wide range of structures. Shibasaki and co-workers reported an interesting intramolecular cyclization for the efficient synthesis of bicyclic amidines [6a] and highlighted the challenge in synthesizing chiral bicyclic amidines. The present study focuses on a ring opening of the VCP, a Ritter-type reaction, and a subsequent cyclization in one pot to obtain enantiomerically pure amidines. In our preliminary studies, we investigated the reaction of (+)-2-carene (3) with chloramine-T (1) in the presence of a catalytic amount of phenyltrimethylammonium tribromide (2; PTAB) using acetonitrile as the solvent (Scheme 1). It resulted in the serendipitous formation of the optically pure [4.4.0] bicyclic amidine 4 a in good yield, rather than the expected aziridine derivative A. 8] The structure of 4 a was confirmed unambiguously by X-ray crystallography (see Scheme 4). Although, VCP derivatives have been shown to undergo a Ritter-type reaction under strongly acidic conditions, [8] the reaction has not been utilized as an approach for the synthesis of amidines. The reaction was optimized by varying the electrophilic halogen source, which was used as the catalyst, to get the bicyclic amidine 4 a as the exclusive product.

Journal of the American Chemical Society, 2012

Helvetica Chimica Acta, 2008

The synthesis of chirally pure b-blockers was successfully achieved via hydrolytic kinetic resolution of butyl (AE)-4-(oxiran-2-ylmethoxy)benzeneacetate ((AE)-1) and (AE)-4-(oxiran-2-ylmethoxy)benzeneacetonitrile ((AE)-2) in the presence of bimetallic chiral [Co(salen)]-type complexes. The newly synthesized bimetallic chiral [Co(salen)]-type complexes exhibited excellent enantioselectivities of up to > 98% ee in good yields (Tables 1-3).

Tetrahedron Letters, 1996

Organic Letters, 2008

Pop-directed asymmetric deprotonation of benzylic amines using [n-BuLi/(-)-sparteine] provides an efficient method for the synthesis of chiral NC r and NC r,r′ derivatives with total selectivity with respect to competing allylic and ortho lithiation. The method described herein offers a straightforward route of accessing chiral N-Pop-protected nitrogen heterocycles.

Angewandte Chemie International Edition, 2006

The aldehyde is arguably the most versatile carbonyl functionality. Furthermore, it is more active than any other carbonyl functionality toward a plethora of nucleophilic reactions. This unique combination of functional versatility and activity renders chiral aldehydes highly valuable intermediates in asymmetric synthesis. The emergence of numerous catalytic enantioselective reactions that involve aldehydes as either nucleophiles or electrophiles further enhances the synthetic value of chiral aldehydes. Enantioselective transformations of the readily available prochiral aldehydes are now emerging as a fundamentally important approach toward optically active aldehydes. In particular, great strides have been made in the development of enantioselective bond formations with the a-carbon atom of prochiral aldehydes with chiral enamine catalysis, enantioselective cycloadditions and Friedel-Crafts reactions with chiral immonium catalysis, and conjugate additions of aryl boronic acids and silyl nitronates to a,b-unsaturated aldehydes by chiral transition-metal catalysis and chiral phase-transfer catalysts, respectively. Despite its synthetic importance, the highly enantioselective and general conjugate addition of carbonyl donors to a,b-unsaturated aldehydes remains elusive, even with considerable efforts. [6] Herein, we wish to report significant progress toward the development of such a reaction with cinchona-alkaloid-derived organic catalysts.

Journal of the American Chemical Society, 2013

The synthesis of a novel supramolecular tetrahedral assembly of K12Ga4L6 stoichiometry is reported. The newly designed chiral ligand exhibits high diastereoselective control during cluster formation, leading exclusively to a single diastereomer of the desired host. This new assembly also exhibits high stability toward oxidation or a low pH environment, and is a more robust and efficient catalyst for asymmetric organic transformations of neutral substrates.