No abstract

Stereodefined four-membered rings are common motifs in bioactive molecules and versatileintermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh-cyclobutyl intermediates undergo chain-walking or C-H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adapted by synthetic and medicinal chemists, and while the carbometallation approach is here exemplified with Rh and arylboronic acids, it is likely applicable to other metals and nucleophiles.

Herein, we describe a rhodium‐catalyzed enantio‐ and diastereoselective Suzuki–Miyaura cross‐coupling between racemic fused bicyclic allylic chlorides and boronic acids. The highly stereoselective transformation allows for the coupling of aryl, heteroaryl, and alkenyl boronic acids and gives access to functionalized bicyclic cyclopentenes, which can be converted into other five‐membered‐ring scaffolds with up to five contiguous stereocenters. Preliminary mechanistic studies suggest that these reactions occur with overall retention of the relative stereochemistry and are enantioconvergent for pseudo‐symmetric allylic chloride starting materials. In addition, a bicyclic allylic chloride starting material without pseudo‐symmetry undergoes a highly enantioselective regiodivergent reaction.

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo-and enantioselective Rh-catalyzed Suzuki−Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio-and diastereoselective Pd-catalyzed Tsuji−Trost reaction with an enolate surrogate.

The iridium-catalyzed asymmetric allylic substitution under biphasic conditions is reported. This approach allows the use of various unstable and/or volatile nucleophiles including hydrazines, methylamine, tbutyl hydroperoxide, N-hydroxylamine, α-chloroacetaldehyde and glutaraldehyde. This transformation provides rapid access to a broad range of products from simple starting materials in good yields and up to >99% ee and 20:1 d.r. Additionally, these products can be elaborated efficiently into a diverse set of cyclic and acyclic compounds, bearing up to four stereocenters.

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known.

Tropane derivatives are extensively used in medicine, but catalytic asymmetric methods for their synthesis are underexplored. Here, we report Rh-catalyzed asymmetric Suzuki–Miyaura-type cross-coupling reactions between a racemic N -Boc-nortropane-derived allylic chloride and (hetero)aryl boronic esters. The reaction proceeds via an unexpected kinetic resolution, and the resolved enantiopure allyl chloride can undergo highly enantiospecific reactions with N-, O-, and S-containing nucleophiles. The method was applied in a highly stereoselective formal synthesis of YZJ-1139(1), a potential insomnia treatment that recently completed Phase II clinical trials. Our report represents an asymmetric catalytic method for the synthesis of YZJ-1139(1) and related compounds.

The iridium-catalyzed asymmetric allylic substitution under biphasic conditions is reported. This approach allows the use of various unstable and/or volatile nucleophiles including hydrazines, methylamine, t-butyl hydroperoxide, Nhydroxylamine, α-chloroacetaldehyde and glutaraldehyde. This transformation provides rapid access to a broad range of products from simple starting materials in good yields and up to >99% ee and 20:1 d.r.. Additionally, these products can be elaborated efficiently into a diverse set of cyclic and acyclic compounds, bearing up to four stereocenters.Enantioselective, transition metal-catalyzed allylic substitution has emerged as a powerful tool for the synthesis of chiral building blocks from simple starting materials and a wide range of nucleophiles. 1 The electrophilic nature of the η3-organometal intermediate typically restricts the conditions to non-nucleophilic organic solvents and with few exceptions prescribes rigorous exclusion of water. 2 Yet, there are a number of highly reactive and/or unstable small molecules such as chloroacetaldehyde, hydrazines or N-hydroxylamine that due to their reactivity or limited stability in pure form are stored, sold, and most safely handled as aqueous solutions. To date, only protected versions of these reagents including hydroxamic acids and hydrazones have been employed in transition metal-catalyzed allylic substitution. 2d,3 Developing methods which employ the commercially available aqueous solutions of these unstable molecules, however, would significantly expand the synthetic utility of enantioselective catalysis.In general, organocatalytic methods based on enamine catalysis or hydrogen bonding catalysts have been shown to be compatible with aqueous media. 4 For instance, aqueous chloroacetaldehyde has been employed as an electrophile in enzymatic or organocatalytic aldol reactions but its use as an nucleophile remains elusive. 5 In the field of asymmetric transition-metal catalysis, biphasic systems for enantioselective oxidations 6 and hydrogenations 7 have garnered significant attention, but transformations generating carbon-carbon bonds under aqueous conditions remain scarce. 8 Herein we report the asymmetric substitution reaction of racemic allylic alcohols with aqueous nucleophiles such as hydrazines, N-hydroxylamines, and α-halo-acetaldehydes catalyzed by a chiral Ir(P,olefin) complex under aqueous biphasic conditions (Scheme 1). The transformations employ aqueous solutions that the reagents are supplied in, and thus avoid laborious extraction and dehydration techniques. 9 Our approach delivers products in good yields and high regio-and enantioselectivities for nucleophiles that have been rarely employed to date. Scheme 1. Iridium-Catalyzed Allylic Substitution Using Nucleophiles or their Hydrates in Aqueous Solutions.