Stereoselective Conjugate Addition Research Articles

Enantio- and Diastereoselective Variations on α-Iminonitriles: Harnessing Chiral Cyclopropenimine-Thiourea Organocatalysts.

Chiral 1-pyrrolines containing a nitrile motif serve as crucial structural scaffolds in biologically active molecules and exhibit diversity as building blocks owing to their valuable functional groups; however, the asymmetric synthesis of such compounds remains largely unexplored. Herein, we present an enantio- and diastereoselective method for the synthesis of α-chiral nitrile-containing 1-pyrroline derivatives bearing vicinal stereocenters through the design and introduction of chiral cyclopropenimine-based bifunctional catalysts featuring a thiourea moiety. This synthesis entails a highly stereoselective conjugate addition of α-iminonitriles to a wide array of enones, followed by cyclocondensation, thereby affording a series of cyanopyrroline derivatives, some of which contain all-carbon quaternary centers. Moreover, we demonstrate the synthetic utility of this strategy by performing a gram-scale reaction with 1% catalyst loading, along with a variety of chemoselective transformations of the product, including the synthesis of a vildagliptin analogue. Finally, we showcase the selective synthesis of all four stereoisomers of the cyanopyrroline products through trans-to-cis isomerization, highlighting the versatility of our approach.

Asymmetric Total Syntheses of Euphol and Tirucallol.

Asymmetric de novo syntheses of euphol and tirucallol have been accomplished by way of a concise sequence of chemical steps featuring several modern stereoselective transformations. The preparative solution described for these complex problems in natural product synthesis departs significantly from biomimetic polyene cyclization chemistry, which has been leveraged to address related tetracyclic triterpenoid targets. In particular, a diastereoselective Friedel-Crafts-type cyclization was employed to establish a tetracycle bearing a stereodefined quaternary center at C9 (steroid numbering) that provided access to intermediates of relevance for introducing the C10 and C14 quaternary centers by sequential stereospecific 1,2-alkyl shifts (C9 → C10 and C15 → C14). Finally, the stereodefined C17 side chain was introduced in a single step by late-stage stereoselective conjugate addition to an intermediate possessing a D-ring enone. Notably, these de novo asymmetric syntheses are the first of their kind, providing completely synthetic access to enantiodefined euphane and tirucallane systems. Overall, each synthesis has been accomplished in fewer than 20 linear chemical steps from a simple Hajos-Parrish-derived ketone through a sequence that features just 15 chromatographic operations.

Tripeptide Organocatalysts for Stereoselective Conjugate Addition Reactions with N‐Heterocyclic Substituents

AbstractN‐heterocyclic moieties are abundant among pharmaceuticals and agrochemicals, but a challenge for metalorganic and organocatalytic transformations. We present tripeptides of the type H‐Pro‐Pro‐Xaa as catalysts for stereoselective conjugate addition reactions between N‐heterocyclic substituted aldehydes and electrophiles. Alkyl substituents at the N‐terminal proline, the reactive site, were crucial for high chemo‐ and stereoselectivity. Different N‐heterocyclic moieties, even at both reaction partners, were readily tolerated and products were obtained in yields of 61–95% and enantioselectivities of up to 98% ee.magnified image

Stereoselective Conjugate Addition-Enamination of α-Linear N-tert-Butanesulfinyl Ketimines with Nitroolefins

Abstract N-Sulfinyl metalloenamines, generated by deprotonating α-linear N-tert-butanesulfinyl ketimines, reacted with nitroalkenes via stereoselective conjugate addition to give Michael adducts with opposite stereochemistry to that obtained using α-branched sulfinylketimines. In the presence of excess base (2.5 equiv t-BuOK), the adducts derived from α-linear ketimines were further stereoselectively deprotonated to afford the corresponding kinetically favorable N-sulfinyl (Z)-enamine derivatives in good yields with good stereoselectivities. A reaction model was proposed to rationalize the observed stereochemistry.

Asymmetric Direct Vinylogous Conjugate Addition of Substituted Furanone Derivatives to (E)‐ and (Z)‐Benzoyl Acrylonitriles Using Organocatalysts

AbstractDiaminomethylenemalononitrile organocatalysts efficiently promoted the asymmetric direct vinylogous conjugate addition of α‐angelica lactone to (E)‐ and (Z)‐benzoyl acrylonitrile derivatives. The synthesized products bear vicinal tertiary and quaternary stereogenic centers with excellent enantioselectivities (up to 98% ee). This report is the first successful example of the stereoselective conjugate addition using (Z)‐benzoyl acrylonitriles as Michael acceptor.

Peptide-Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C-Substituted Maleimides.

Catalytic stereoselective additions with maleimides are useful one‐step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C‐substituted. We present the tripeptide H‐Pro‐Pro‐Asp‐NHC12H25 as a catalyst for conjugate addition reactions between aldehydes and C‐substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.

Remote asymmetric conjugate addition catalyzed by a bifunctional spiro-pyrrolidine-derived thiourea catalyst

A novel spiro-pyrrolidine (SPD)-derived bifunctional thiourea catalyst has been developed and used in a stereoselective conjugate addition of furfurals to β,γ-unsaturated α-ketoesters.

Stereoselective Conjugate Addition of the Lithium Anion of N-Allyl Imine to Unsaturated Esters: Application to the Enantiospecific Total Synthesis of (-)-Epibatidine.

A regio- and diastereoselective conjugate addition of the lithium anion of N-allyl imine (prepared from allylamine and benzophenone) to α,β-unsaturated esters in good yields is reported. The reaction was general and provided the γ-amino esters resulting from the regioselective C-C bond formation between the α-carbon to the nitrogen in the imine and the β-carbon of the unsaturated ester. Synthetic utility of the formed products was illustrated in the nonracemic total synthesis of the bioactive alkaloid (-)-epibatidine.

Asymmetric Total Synthesis of Fawcettimine-Type Lycopodium Alkaloid, Lycopoclavamine-A.

An asymmetric total synthesis of lycopoclavamine-A (1), a structurally unique fawcettimine-type Lycopodium alkaloid, was achieved via a stereoselective Pauson-Khand reaction and a stereoselective conjugate addition to construct a quaternary carbon center at C-12.

Stereoselective conjugate addition of ketones to alkylidene malonates using thiourea-sulfonamide organocatalyst.

In this study, stereoselective conjugate addition of ketones to alkylidene malonates using organocatalyst has been developed. The reaction in the presence of 20mol% of a novel thiourea-sulfonamide organocatalyst afforded conjugate adducts in moderate to high yields (up to 81%) under mild reaction conditions. Excellent diastereoselectivity (up to 98:2 dr) and enantioselectivity (up to 88% ee) were achieved.

Reactivity of Steroidal 1-Azadienes toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids.

The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an initial stereoselective conjugate addition of the in situ generated enamine to the steroidal 1-azadiene. The developed diastereoselective synthetic methodology is a novel approach to a new class of chiral pentacyclic and hexacyclic steroids.

Efficient Syntheses of Quinolizidine-Type Poison-Frog Alkaloids via Michael-Type Conjugate Addition

Efficient and flexible syntheses of 1,4-disubstituted quinolizidine-type poison-frog alkaloids using the highly stereoselective Michael-type conjugate addition reaction as the key step are described. The 1,4-disubstituted quinolizidine poison-frog alkaloids 233A, 235U and 251AA are reported.

Organocatalytic stereoselective conjugate addition of 3-substituted oxindoles with in situ generated ortho-quinone methides

A novel method for the stereoselective conjugate addition of 3-substituted oxindoles to in situ generated o-QMs was described. This process was catalyzed efficiently by a cinchonidine-derived squaramide catalyst in oil-water phase, furnishing the corresponding 3,3-disubsituted oxindole derivatives in moderate to high yields (up to 98%) with high stereoselectivities (up to 95% ee, 15.4:1 dr). The utility of this reaction was also investigated by the gram-scale synthesis and derivatization of one of the products.

Enantioselective copper-catalyzed conjugate additions of in situ generated organozirconium reagents to N-heterocyclic Michael acceptors

Stereoselective conjugate additions of organometallic reagents provide access to many useful chiral compounds. In this work, we have studied the enantioselective Cu-catalyzed conjugate addition of organozirconium reagents, which were generated in situ by hydrozirconation of alkenes. We show that N-heterocyclic Michael acceptors, represented by unsaturated lactams and 2,3-dihydropyridin-4(1H)-ones can be useful substrates for Cu-catalyzed conjugate additions of organozirconium reagents. Phosphorus ligands screening identified Feringa's phosphoramidite as the most active and enantioselective ligand for this transformation, which afforded corresponding conjugate addition products with an enantiomeric purity of up to 92:8 e.r. The absolute configuration of one of the conjugate addition products was established by comparison of DFT calculated and experimental electronic CD spectra. The study also showed that mildly reactive organozirconium reagents combined with relatively unreactive Michael acceptors afford typically conjugate addition products in medium yields. DFT calculations of LUMO maps also supported non-reactivity of heterocyclic Michael acceptors. LUMO maps showed decreasing electrophilicity at the β-carbon due to donor substituents present near unsaturated carbonyl scaffold.

N-methylative aziridine ring opening and the synthesis of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile

The preparation of (S)-3-methylamino-3-[(R)-pyrrolidin-3-yl]propanenitrile (1), a key fragment of fluoroquinolone antibiotic PF-00951966 and others was achieved by N-methylative aziridine ring opening, addition of methyl group at the ring nitrogen, and ring-opening via a cyanide nucleophile in a single operation starting from bicyclic (R)-2-[(R)-pyrrolidine-3-yl]aziridine. The starting compound was elaborated from stereoselective conjugate addition of nitromethane to (R)-aziridine-2-yl acrylate followed by selective reduction without breaking the aziridine ring.

Bifunctional Quaternary Ammonium Salts Catalyzed Stereoselective Conjugate Addition of Oxindoles to Electron-Deficient β-Haloalkenes.

A highly Z-selective asymmetric conjugate addition of 3-substituted oxindoles to β-haloalkene ketones/esters catalyzed by readily available chiral bifunctional quaternary ammonium salts is reported. This reaction provides efficient access to a range of 2-oxoindole derivatives bearing a thermodynamically unstable Z-olefin structure and a chiral quaternary carbon center in high yields (up to 90%) and with good to high stereoselectivities (up to >19:1 Z/E and 91% ee) under mild conditions.

Flexible Syntheses of 5,8-Disubstituted Indolizidine Poisonous-Frog Alkaloids via a Michael-Type Conjugate Addition

The efficient and flexible syntheses of 5,8-disubstituted indolizidine poisonous-frog alkaloids is described using a highly stereoselective Michael-type conjugate addition reaction as the key step. In this work, syntheses of the 5,8-disubstituted indolizidine poisonous-frog alkaloids (–)-231C, (–)-221I and the proposed structure for (–)-193E are reported.

An unprecedented stereoselective base-induced trimerization of an α-bromovinylsulfone.

A unprecedented base-induced trimerization of bromovinylsulfone 1 afforded the cyclohexene 6 as a single diastereoisomer. Optimization of this reaction gave the adduct 6 in 49% yield. A mechanistic rationale for the trimerization involving consecutive SN2' additions and [3,3]-rearrangements and a final stereoselective intramolecular conjugate addition is proposed and supported by M06-2X density functional theory calculations.

ChemInform Abstract: Peptide‐Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide.

AbstractThe tripeptide H‐dPro‐Pro‐Asn‐NH2 is presented as catalyst for asymmetric conjugate addition reactions of aldehydes to maleimide.

Synthetic studies on enfumafungin: stereoselective synthesis of the CD ring segment

The stereoselective synthesis of the right-hand segment of enfumafungin, a potent antifungal agent isolated from a Hormonema sp., was achieved. The contiguous two quaternary carbon atoms at the angular positions of the trans-fused CD ring system was constructed through the stereoselective reduction of 4-cyano-3,4-dimethyl-2-cyclohexen-1-one and the Johnson–Claisen rearrangement. After elongation of the side chains, the D ring was formed via a stereoselective intramolecular conjugate addition reaction which was originally developed by our laboratory.