Chiral Cyclopentane Research Articles

A concise and scalable chemoenzymatic synthesis of prostaglandins

Prostaglandins have garnered significant attention from synthetic chemists due to their exceptional biological activities. In this report, we present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps. Notably, the common intermediate bromohydrin, a radical equivalent of Corey lactone, is chemoenzymatically synthesized in only two steps, which allows us to complete the synthesis of prostaglandin F2α in five steps on a 10-gram scale. The chiral cyclopentane core is introduced with high enantioselectivity, while the lipid chains are sequentially incorporated through a cost-effective process involving bromohydrin formation, nickel-catalyzed cross-couplings, and Wittig reactions. This cost-efficient synthesis route for prostaglandins holds the potential to make prostaglandin-related drugs more affordable and facilitate easier access to their analogues.

Copper catalyzed diastereoselective and enantioselective hydroborylation of cyclopentenylcarboxyesters

Cu-catalyzed asymmetric hydroborylation of cyclopentenylcarboxyesters.

Construction of Cyclopentanes Consisting of Five Stereocenters via NHC-Catalyzed Cascade Reactions of Enals with Oxindole-Dienones.

Despite the widespread presence of the chiral cyclopentane motif, the asymmetric synthesis of cyclopentanes containing five stereocenters remains a formidable challenge. Here, we present an N-heterocyclic carbene (NHC)-catalyzed cascade reaction of enal and oxindole-dienone, which allows access to spiroxindole cyclopentanes featuring a complete set of chiral centers on the five-membered carbocycle. This strategy, characterized by the formation of multiple bonds and chiral centers, demonstrates a broad substrate scope, exclusive diastereoselectivity, and up to 99:1 er.

Synthesis of the eight-membered carbocycle of brachialactone by intramolecular Mizoroki-Heck reaction

A synthesis of the BC ring moiety of brachialactone, a fusicoccane-type diterpene isolated from the tropical forage grass Brachiaria humidicola and found to inhibit nitrification by soil microbes, is described. Several precursors including the C ring were synthesized from a known chiral cyclopentane, and then subjected to the conditions for the Mizoroki-Heck reaction. Substrates incorporating vinyl (R = H) or enone (R = COCH3) moieties and incorporating an S configuration at C-2 successfully underwent intramolecular Mizoroki-Heck reaction, giving the BC ring structure of brachialactone.

Modular access to chiral cyclopentanes via formal [2+2+1] annulation enabled by palladium/chiral squaramide relay catalysis

An enantio- and diastereodivergent [2+2+1] annulation reaction of allyl ketones, acidic methylene compounds, and nitroalkenes to assemble highly functionalized cyclopentanes from readily available substances enabled by asymmetric relay catalysis of chiral bifunctional squaramide and palladium complex has been established. This method showcases that allyl ketones can serve as latent 1,2-dication synthons via a linear-selective allylic C–H functionalization and sequential 1,4-conjugated addition, enabling the rapid assembly of cyclopentane skeleton with a broad scope of methylene nucleophiles and nitroalkenes. Notably, chiral bifunctional squaramide catalyst engages in both the intermolecular and intramolecular Michael addition reactions accompanying with a kinetic resolution behavior to amplify the enantioselection. In addition, the stereodivergent synthesis of diastereomers from the resultant chiral cyclopentane derivatives is also accessible by a simple manipulation with base.

Enantioselective Synthesis of SpirothiazolonesviaCooperative Catalysis

AbstractCooperative amino‐ and palladium catalysis utilizing heterocyclic systems containing strongly coordinating and adsorptive sulfur atom remains an underdeveloped area. Herein, we describe an enantioselective cyclization of enals with thiazole derivatives catalyzed with the combination of achiral Pd(0) complexes and chiral secondary amines. Chiral spirocyclic thiazolones were produced in yields ranging from 41% to 98% with stereoselectivities (from 5:1 to 12:1 dr, and 95–99% ee). Moreover, the developed strategy allows access to highly substituted chiral cyclopentane derivatives by additional transformations of spirocyclic thiazolones.magnified image

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp3)-H Activation.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp3)-H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp3)-H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp3)-H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp3)-H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

Total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α via three-component coupling

The asymmetric total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α from a common key intermediate are described. The key intermediate, which has a chiral cyclopentane backbone possessing suitable functional groups with required stereochemistry for both side chains, was prepared from (R)-4-silyloxy-2-cyclopentenone through a three-component coupling reaction. The Wittig reaction, Nozaki-Hiyama-Kishi (NHK) coupling and cross metathesis completed the synthesis of PGF2α, 6,15-diketo-PGF1α and 6-keto-PGF1α.

Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst.

An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the ω-side chain was generated by prolinate-anion-mediated α-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality.

Asymmetric [3+2] Photocycloadditions of Cyclopropanes with Alkenes or Alkynes through Visible-Light Excitation of Catalyst-Bound Substrates.

The herein reported visible-light-activated catalytic asymmetric [3+2] photocycloadditions between cyclopropanes and alkenes or alkynes provide access to chiral cyclopentanes and cyclopentenes, respectively, in 63-99 % yields and with excellent enantioselectivities of up to >99 % ee. The reactions are catalyzed by a single bis-cyclometalated chiral-at-metal rhodium complex (2-8 mol %) which after coordination to the cyclopropane generates the visible-light-absorbing complex, lowers the reduction potential of the cyclopropane, and provides the asymmetric induction and overall stereocontrol. Enabled by a mild single-electron-transfer reduction of directly photoexcited catalyst/substrate complexes, the presented transformations expand the scope of catalytic asymmetric photocycloadditions to simple mono-acceptor-substituted cyclopropanes affording previously inaccessible chiral cyclopentane and cyclopentene derivatives.

Asymmetric [3+2] Photocycloadditions of Cyclopropanes with Alkenes or Alkynes through Visible‐Light Excitation of Catalyst‐Bound Substrates

AbstractThe herein reported visible‐light‐activated catalytic asymmetric [3+2] photocycloadditions between cyclopropanes and alkenes or alkynes provide access to chiral cyclopentanes and cyclopentenes, respectively, in 63–99 % yields and with excellent enantioselectivities of up to >99 % ee. The reactions are catalyzed by a single bis‐cyclometalated chiral‐at‐metal rhodium complex (2–8 mol %) which after coordination to the cyclopropane generates the visible‐light‐absorbing complex, lowers the reduction potential of the cyclopropane, and provides the asymmetric induction and overall stereocontrol. Enabled by a mild single‐electron‐transfer reduction of directly photoexcited catalyst/substrate complexes, the presented transformations expand the scope of catalytic asymmetric photocycloadditions to simple mono‐acceptor‐substituted cyclopropanes affording previously inaccessible chiral cyclopentane and cyclopentene derivatives.

Asymmetric Synthesis of Chiral Cyclopentanes Bearing an All-Carbon Quaternary Stereocenter by Zirconium-Catalyzed Double Carboalumination.

Herein, we report a zirconium-catalyzed enantio- and diastereoselective inter/intramolecular double carboalumination of unactivated 2-substituted 1,5-dienes, which provides efficient and direct access to chiral cyclopentanes through the generation of two stereocenters, including one all-carbon quaternary stereocenter, generally with excellent diastereo- and high enantioselectivity. This tandem carboalumination process creates two new C-C bonds as well as one C-Al bond, which can be oxidized in situ with O2 or hydrolyzed. Furthermore, the obtained chiral cyclopentanes can be readily functionalized to provide various chiral compounds.

Asymmetric Synthesis of Chiral Cyclopentanes Bearing an All‐Carbon Quaternary Stereocenter by Zirconium‐Catalyzed Double Carboalumination

AbstractHerein, we report a zirconium‐catalyzed enantio‐ and diastereoselective inter/intramolecular double carboalumination of unactivated 2‐substituted 1,5‐dienes, which provides efficient and direct access to chiral cyclopentanes through the generation of two stereocenters, including one all‐carbon quaternary stereocenter, generally with excellent diastereo‐ and high enantioselectivity. This tandem carboalumination process creates two new C−C bonds as well as one C−Al bond, which can be oxidized in situ with O2 or hydrolyzed. Furthermore, the obtained chiral cyclopentanes can be readily functionalized to provide various chiral compounds.

Functionalized Propellanes, Azetidines, Cyclobutanes, and Chiral Cyclopentanes

Functionalized Propellanes, Azetidines, Cyclobutanes, and Chiral Cyclopentanes

ChemInform Abstract: Dipeptide‐Derived Multifunctional Phosphonium Salt as a Catalyst to Synthesize Highly Functionalized Chiral Cyclopentanes.

AbstractThe reaction affords cyclopentane structures with 3 contiguous stereocenters and a quaternary carbon atom.

ChemInform Abstract: Rhodium‐Catalyzed Desymmetrization by Hydroformylation of Cyclopentenes: Synthesis of Chiral Carbocyclic Nucleosides.

AbstractA Rh‐catalyzed desymmetric hydroformylation of 3‐substituted cyclopentenes constitutes an efficient approach to chiral cyclopentane carboxyaldehydes.

Dipeptide-derived multifunctional phosphonium salt as a catalyst to synthesize highly functionalized chiral cyclopentanes

Asymmetric tandem Michael–Michael reactions between 2-substituted malonates and low reactive enones have been achieved by using novel dipeptides-derived phosphonium salts, affording the synthetically useful and highly functionalized chiral cyclopentanes with good yields, diastereoselectivities and high enantioselectivities.

Rhodium-Catalyzed Desymmetrization by Hydroformylation of Cyclopentenes: Synthesis of Chiral Carbocyclic Nucleosides.

Excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (up to >99:1 d.r.) have been achieved in the desymmetrization of cyclopentenes by catalytic hydroformylation. This novel methodology provides an efficient and concise synthetic route to chiral cyclopentane carboxaldehydes. The key intermediate, (1S,3S)-(3-hydroxymethyl)cyclopentanol, for the synthesis of carbocyclic-ddA was obtained in three steps.

Rhodium‐Catalyzed Desymmetrization by Hydroformylation of Cyclopentenes: Synthesis of Chiral Carbocyclic Nucleosides

AbstractExcellent enantioselectivities (up to 97 % ee) and diastereoselectivities (up to >99:1 d.r.) have been achieved in the desymmetrization of cyclopentenes by catalytic hydroformylation. This novel methodology provides an efficient and concise synthetic route to chiral cyclopentane carboxaldehydes. The key intermediate, (1S,3S)‐(3‐hydroxymethyl)cyclopentanol, for the synthesis of carbocyclic‐ddA was obtained in three steps.

Stereoselective synthesis and molecular modeling of chiral cyclopentanes

The reaction of 3-methyseleno-2-methylselenomethyl-propene with benzyl 2,3-anhydro-4-O-triflyl-β-L-ribopyranoside provides a major convenient enantiomeric product of 1-methylene-(benzyl3,4-dideoxy-α-D-arabinopyranoso)-[3,4-c]-cyclopentane, with benzyl-2,3-anhydro-4-deoxy-4-C-(2-methyl- propen-3-yl)-α-D-lyxopyranoside as a minor product. While the reaction of 3-methyseleno-2-[methylselenomethyl]-propene with benzyl 2,3-anhydro-4-O-triflyl-α-D-ribopyranoside produces a good yield of benzyl-2,3-anhydro-4-deoxy-4-C-(2-methylpropen-3-yl)-α-D-lyxo-pyranoside. Molecular modeling and molecular dynamics simulations indicate that the intermediate in the reaction of the β-L sugar frequently occupies an optimal conformation that leads to the formation of cyclopentane, while the intermediate in the reaction of the α-D sugar has a very small probability. The results point to the dominant role of the β-L sugar intermediate in controlling the cyclopentane formation.