Adjacent Stereogenic Centers Research Articles

Construction of Spiro[pyrrolidine-azlactone] via [2 + 3] Cycloaddition of Alkylidene Azlactone with Trifluoromethylated Imine.

A Ag-catalyzed [2 + 3] cycloaddition of alkylidene azlactones with trifluoromethylated imines has been documented, providing spiro[pyrrolidine-azlactones] bearing four adjacent stereogenic centers with good yields and excellent diastereoselectivities. Catalytic asymmetric cycloaddition has also been developed with good yields and excellent enantioselectivities. Further gram-scale preparation and synthetic transformation to pyrrolidine derivative showed the good practicality and applicability of this reaction.

Nickel-Catalyzed Enantioconvergent and Diastereoselective Allenylation of Alkyl Electrophiles: Simultaneous Control of Central and Axial Chirality.

In recent years, remarkable progress has been described in the development of methods that simultaneously control vicinal stereochemistry, wherein both stereochemical elements are central chirality; in contrast, methods that control central and axial chirality are comparatively rare. Herein we report that a chiral nickel catalyst achieves the enantioconvergent and diastereoselective coupling of racemic secondary alkyl electrophiles with prochiral 1,3-enynes (in the presence of a hydrosilane) to generate chiral tetrasubstituted allenes that bear an adjacent stereogenic center. A carbon-carbon and a carbon-hydrogen bond are formed in this process, which provides good stereoselectivity and is compatible with an array of functional groups.

Dihydro-10H-indeno[1,2-b]benzofurans and Tetrahydroindeno[1,2-c]isochromenes via Stereoselective Intramolecular Carbocation Cascade Cyclization.

Nazarov cyclization of the (E)-(2-stilbenyl)methanols under the catalysis of p-TsOH immobilized on silica (PTS-Si) proceeded to give the corresponding indanyl cation with the exclusive trans relationship at the two newly formed adjacent stereogenic centers. The ensuing intramolecular nucleophilic addition by the MOM-protected phenol (m = 0) or benzyl alcohol (m = 1) furnished the Indane-fused benzofuran [5/5] or isochroman [5/6] system, respectively, with the exclusive cis stereocontrol at the two-carbon ring junction. Thus, in a single step, from nonchiral starting materials, the intramolecular cascade carbocation cyclization (CCC) furnished the [5/5] or [5/6] oxygen-containing Indane fused-ring systems in moderate to good yields with excellent stereoselectivity on all three contiguous stereogenic centers.

Bifunctional Squaramide-Catalyzed Asymmetric Cascade Reaction of Benzothiazoles with 2-Nitroallylic Acetates or Nitroenynes.

We describe here an organocatalytic asymmetric cascade formal [3 + 3] cycloaddition of benzothiazoles with 2-nitroallylic acetates and nitroenynes. This dearomative methodology provided a facile and efficient strategy for the construction of a broad range of valuable benzothiazolopyridines bearing two adjacent stereogenic centers in moderate to good yields with good to excellent stereocontrol.

Copper‐Catalyzed Asymmetric 1,6‐Addition of Borylalkene‐Derived Nucleophiles to para‐Quinone Methides

AbstractHerein, we report the catalytic 1,6‐addition of chiral alkyl copper nucleophiles, in‐situ generated from borylalkenes and a copper‐hydride catalyst under mild conditions. Chemo‐ and stereoselective control was crucial in this reductive coupling process of borylalkenes and para‐quinone methides, sequentially forming adjacent stereogenic centers with good diastereo‐ and enantioselectivity. Through the multicomponent and catalytic tandem reactions, asymmetric 1,6‐adducts of p‐quinone methides were efficiently synthesized.magnified image

Stereodivergent dehydrative allylation of β-keto esters using a Ru/Pd synergistic catalyst

α-Alkylation of a β-keto ester is a frequently used reaction for carbon–carbon bond formation. However, extension to a stereoselective reaction remains a significant challenge, because the product easily racemizes under acidic or basic conditions. Here, we report a hybrid system consisting of Pd and Ru complexes that catalyzes the asymmetric dehydrative condensation between cinnamyl-type allylic alcohols and β-keto esters. α-Non-substituted β-keto ester can be allylated to afford an α-mono-substituted product with high regio-, diastereo-, and enantioselectivity. No epimerization occurs owing to the nearly neutral conditions, which is achieved by a rapid proton transfer from Pd-enolate formation to Ru π-allyl complex formation. Four diastereomers can be synthesized on demand by changing the stereochemistry of the Pd or Ru complex. Eight stereoisomers with three adjacent stereogenic centers can be synthesized by employing diastereoselective reduction of the ketone in the products. The formal synthesis of (+)-pancratistatin demonstrates the utility of the reaction.

Construction of novel penta cyclic indolo-furo[3,2-c]quinoline and dihydrochromeno-furo[2,3-b]indol via sequential annulation strategy

An efficient, rapid and green synthesis of indolo-furo-quinoline and chromeno-furo-indoles has been developed by one-pot reaction of 2,4-quinolinediol or 4-hydroxycoumarin, phenylglyoxal and aromatic amine in the presence of acetic acid as an reaction medium cum promoter at room temperature. This scalable tandem reaction affords a series of novel dihydro-indolo-furo-quinoline and dihydro-chromeno-furo-indole derivatives with two adjacent stereogenic centers in good to excellent yields and with high regioselectivity and stereoselectivity. Moreover, this cascade reaction provides a distinct Knoevenagel, Michael and through intramolecular cyclization in sequential manner under mild reaction conditions to access the diversely decorated indolo-furo-quinoline and chromeno-furo-indoles of considerable importance to natural product synthesis and medicinal chemistry.

Asymmetric synthesis of pyrrolo[2,3–b]indole scaffolds by organocatalytic [3 + 2] dearomative annulation

An organocatalytic approach for the stereoselective synthesis of pyrrolo[2,3–b]indoles is presented. The developed methodology is based on the [3 + 2] dearomative annulation reaction between 3-nitroindoles and fumaric acid amide esters. Products bearing three adjacent stereogenic centers, one being quaternary, were formed with excellent yields, good diastereoselectivities and decent enantioselectivities.

Synthesis of the C4–C16 Polyketide Fragment of Portimines A and B

Stereoselective synthesis of the C4-C16 polyketide fragment of portimines A and B is reported, enabled by our previously established method for the stereoselective synthesis of syn-α,α'-dihydroxyketones. The preparation of this advanced fragment provides insights useful for the total synthesis of portimines A and B. An asymmetric Evans aldol reaction was used to install the C10-C11 adjacent stereogenic centers before incorporation of indantrione, followed by epoxidation and epoxide opening to forge the challenging syn-α,α'-dihydroxyketone functionality.

Transformation from triple helicene to double helicene embedding adjacent stereogenic carbon atoms and axial stereogenicity.

Transformation of triple helicene (TH) to double helicene (DH) with adjacent stereogenic carbon atoms and axial stereogenicity was achieved by the unexpected conjugate addition to the central aromatic ring of TH-1. We also studied the boundary at which different reactivities to addition reactions occur in some helicenes with different π-extension.

Ring-Strain-Enabled Catalytic Asymmetric Umpolung C-O Bond-Forming Reactions of 1,2-Oxazetidines for the Synthesis of Functionalized Chiral Ethers.

An unprecedented catalytic asymmetric umpolung C-O bond-forming reaction of N-nosyl 1,2-oxazetidines with β-keto esters has been achieved in the presence of a chiral phase-transfer catalyst, allowing access to a range of highly functionalized chiral ethers bearing quaternary and no adjacent stereogenic centers with high yields, excellent enantioselectivities, and diastereoselectivities (up to 97% ee and 20:1 dr). These versatile products could be flexibly transformed into biologically important chiral fused and spiro morpholines in two steps.

Stereodivergent Synthesis of α-Quaternary Serine and Cysteine Derivatives Containing Two Contiguous Stereogenic Centers via Synergistic Cu/Ir Catalysis.

A stereodivergent preparation of α-quaternary serine/cysteine derivatives incorporating two adjacent stereogenic centers has been developed through Cu/Ir-catalyzed asymmetric allylation of 2-oxazoline-4-carboxylates and 2-thiazoline-4-carboxylates. Tuning the electronic effect is the key to enhancing the reactivity of 2-oxazoline-4-carboxylates and suppressing the undesired β-elimination. The salient feature of this protocol is that all four stereoisomers of α-quaternary serine and cysteine derivatives could be achieved from the identical starting materials through pairwise combination of two distinct chiral catalysts.

Asymmetric catalysis in direct nitromethane-free Henry reactions.

A great number of reports have described asymmetric catalytic Henry reactions using nitromethanes as pronucleophiles, but far more challenging is diastereoselective catalytic Henry reactions using substituted higher nitroalkanes instead of nitromethane to generate chiral β-nitro alcohol scaffolds with four adjacent stereogenic centers in a one-pot operation. This review summarizes the current state and applications of such reactions involving complex nitroalkane coupling with various carbonyl compounds for resolving double chiral centers with high enantio- and diastereoselectivities.

Enantioselective Synthesis of Oxindole‐Derived α‐Aryl‐β‐Amino Acid Derivatives and δ‐Lactams with Homophthalic Anhydrides

AbstractA highly diastereo‐ and enantioselective Mannich reaction of isatin‐derived N‐Boc imines with homophthalic anhydrides is disclosed for the first time, which allows the direct synthesis of a wide range of oxindole‐derived α‐aryl‐β‐amino acids with two adjacent carbon stereogenic centers in a highly stereoselective fashion (up to >95:5 dr & >99% ee). The resulted Mannich adducts can be easily converted to chiral spirocyclic δ‐lactams with retention of the stereoslectivities.magnified image

Asymmetric synthesis of tetrahydropyran[3,2-c]quinolinones via an organocatalyzed formal [3 + 3] annulation of quinolinones and MBH 2-naphthoates of nitroolefin

An efficient asymmetric and enantio-swithchable organocatalytic [3+3] annulation reaction using MBH-2-naphthoates of nitroalkenes and 4-hydroxyquinolin-2(1H)-ones has been developed. Densely substituted tetrahydropyrano[3,2-c]quinolinones scaffolds with two adjacent stereogenic centers are obtained with high yield (up to 95% yield) and good stereoselectivities (up to >20:1 dr and 96% ee) in an enantio-switchable manner. Furthermore, gram scale synthesis was achieved and the nitro group could easily transform into an amino group without any appreciable loss in the diastereo- and enantioselectivity.

Asymmetric Cycloaddition of ortho-Hydroxyphenyl-Substituted para-Quinone Methides and Enamides Catalyzed by Chiral Phosphoric Acid.

A BINOL-based chiral phosphoric acid was employed as an efficient catalyst in enantioselective cycloaddition of ortho-hydroxyphenyl-substituted para-quinone methides and enamides, which gave rise to acetamido-substituted tetrahydroxanthenes with three adjacent stereogenic centers in high yields (up to 99%) and excellent stereoselectivities (up to >99:1 diastereomeric ratio and up to 98% ee).

A Sequential Pd-AAA/Cross-Metathesis/Cope Rearrangement Strategy for the Stereoselective Synthesis of Chiral Butenolides.

A practical and highly enantio- (up to 94:6 er) and diastereoselective (up to >20:1 dr) synthesis of γ-butenolides bearing two adjacent stereogenic centers is reported featuring a sequential direct palladium-catalyzed asymmetric allylic alkylation/( E)-selective cross-metathesis/[3,3]-sigmatropic Cope rearrangement from readily available α-substituted (5 H)-furan-2-ones.

Enantioselective Synthesis of CF3‐Containing 3,2’‐Pyrrolidinyl Spirooxindoles and Dispirooxindoles via Thiourea‐Catalyzed Domino Michael/Mannich [3+2] Cycloaddition Reactions

AbstractAn efficient and practical organocatalytic asymmetric domino Michael/Mannich [3+2] cycloaddition of N‐2,2,2‐trifluoroethylisatin ketimines and arylidene azlactones by using a hydroquinine‐derived thiourea as the catalyst has been disclosed. Under mild conditions, a broad range of CF3‐containing 3,2’‐pyrrolidinyl spirooxindole/ dispirooxindole derivatives bearing four adjacent stereogenic centers including two vicinal spiro quaternary chiral centers were obtained in high yields (up to 99% yield) with excellent diastereoselectivities (>20:1 dr, in all case) and enantioselectivities (up to >99% ee).magnified image

Asymmetric Total Synthesis of (-)-Juvabione via Sequential Ir-Catalyzed Hydrogenations.

(-)-Juvabione, a natural sesquiterpene exhibiting juvenile insect hormone activity, was synthesized constructing the two adjacent stereogenic centers via sequential Ir-catalyzed hydrogenations. The first center is generated by hydrogenation of a styrene-type double bond (99% ee). The successive monohydrogenation of a diene intermediate constitutes the key step, granting high levels of regio- and stereocontrol (94:6 dr). This novel strategy allowed the preparation of (-)-juvabione from simple starting materials in 9 steps and 17% total yield.

Lewis Acid Catalyzed [3+2] Annulation of γ‐Butyrolactone Fused Cyclopropane with Aldehydes/Ketones

The [3+2] annulation reaction of γ‐butyrolactone fused cyclopropanes with aldehydes or ketones under Lewis acid catalysis is described. Compared to their parent donor–acceptor (D–A) cyclopropanes, such fused bicyclic cyclopropanes demonstrated much better reactivity in this type of annulation process, providing accesses to densely substituted γ‐butyrolactone fused tetrahydrofurans bearing multiple adjacent stereogenic centers with a low catalyst loading (1–5 mol‐%), excellent diastereoselectivity, and a broad substrate scope under mild reaction conditions.