Modified Cinchona Alkaloids Research Articles

Inside Cover Picture

An asymmetric [3+2] annulation reaction between Morita−Baylis−Hillman carbonates from trifluoromethyl ketones and cyclic sulfonimines is developed under the catalysis of a modified cinchona alkaloid, and diastereodivergent synthesis can be well realized by simply changing the solvent. More details are given in the article by Chen et al. on page 1185—1189.image

Solvent‐Regulated Diastereodivergent [3 + 2] Annulations of CF3‐Containing Morita−Baylis−Hillman Carbonates with Cyclic Sulfonimines

Comprehensive SummaryA solvent‐regulated diastereodivergent [3 + 2] annulation reaction between Morita‐Baylis‐Hillman carbonates from aryl trifluoromethyl ketones and cyclic sulfonimines is developed under the catalysis of a modified cinchona alkaloid, furnishing diverse polycyclic products bearing vicinal quaternary stereogenic centers with outstanding enantioselectivity and moderate to high diastereoselectivity.

Modified cinchona alkaloid-catalysed enantioselective [4+4] annulations of cyclobutenones and 1-azadienes.

Constructing eight-membered rings, especially in an enantioselective manner, is a challenging task due to unfavorable enthalpic and entropic barriers of the transition states during the formation process. Here we report an asymmetric [4+4] annulation reaction of diverse 1-azadienes and β-substituted cyclobutenones under the catalysis of modified cinchona alkaloids, by the in situ generation of ring-opened ammonium dienolate intermediates. A spectrum of heteroarene- or indene-fused eight-membered lactams are obtained in fair to excellent yields with remarkable enantioselectivities (up to 99% yield, 99% ee).

Review on Asymmetric Transformations with Chiral Phase-Transfer Catalysts

This review focuses onasymmetric transformations with Chiral Phase-Transfer Catalysts and its application. Phase-transfer catalysis is practical methodology for organic synthesis. It is possible to achieve highly enantio selective transformations under phase-transfer conditions for a variety of ─C─C─ ─C─O─ and ─C─N─ bond-forming reactions. The asymmetric transformations using modified cinchona alkaloids, chiral spiro ammonium salts and crown ether are among the primary source of effective chiral phase-transfer catalyst, which allows access to enantiomerically pure unnatural amino acids and synthetically useful adducts containing quaternary stereogenic centers. The advantage of this method is its simple experimental procedure, large chiral pool, mild reaction condition, inexpensive, environmentally benign reagent and use of simple and inexpensive reactants. Nowadays, it appears to be the most important synthetic method used in various fields of organic chemistry, and also found widespread industrial applications. This review summarizes the synthesis application, enantio selective transformation of some selected reaction, biological activities and catalytic activities of Phase-transfer catalysis and especial emphasis is given for organo catalysis. In asymmetric organo catalyst, it is possible to obtain chiral organic products in high enantio enriched form by steric hindrance approach method. The advantage of organic molecules as chiral catalysts complements the traditional organo-metallic and biological approaches to asymmetric catalysis.

Organocatalyzed Dearomative Cycloaddition of 2-Nitrobenzofurans and Isatin-Derived Morita-Baylis-Hillman Carbonates: Highly Stereoselective Construction of Cyclopenta[ b]benzofuran Scaffolds.

The first organocatalyzed asymmetric dearomative cycloaddition between 2-nitrobenzofurans and isatin-derived Morita-Baylis-Hillman carbonates has been developed. Using a modified cinchona alkaloid as the catalyst, a series of structurally diverse cyclopenta[ b]benzofuran derivatives with three contiguous stereocenters, including a spiro-quaternary chiral center, could be smoothly obtained in excellent results (all cases >20:1 dr, up to 99% yield and 98% ee). The utility of this method was showcased by the versatile transformations of the product.

Asymmetric domino 1,6-addition/annulation reaction of 3-cyano-4-alkenyl-2H-chromen-2-ones with isatin-derived MBH carbonates: enantioselective synthesis of 3,3′-cyclopentenylspirooxindoles bearing 2H-chromen-2-ones

An asymmetric domino 1,6-addition/annulation reaction of 3-cyano-4-alkenyl-2H-chromen-2-ones with isatin-derived MBH carbonates was achieved by using a modified cinchona alkaloid as a catalyst.

Origin of and a Solution for Uneven Efficiency by Cinchona Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric Reactions.

Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied classes of organocatalysts, which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist in nature as pseudoenantiomers, which allow cinchona alkaloid-catalyzed reactions to provide high enantioselectivities and yields toward both enantiomers of interest in many reactions. On the other hand, the subtle structural difference between pseudoenantiomeric cinchona alkaloids could also lead to uneven efficiency that severely limits the applicability of some cinchona alkaloid-catalyzed reactions. We describe here the elucidation of the origin of and the consequent development of novel modified cinchona alkaloids to address such a problem in asymmetric imine umpolung reactions by cinchonium salts.

Tertiary Amine‐Catalyzed Difluoromethylthiolation of Morita–Baylis–Hillman Carbonates of Isatins with Zard's Trifluoromethylthiolation Reagent

AbstractIn this paper, we report that a novel tertiary amine‐catalyzed [3+2] annulation between Morita–Baylis–Hillman (MBH) carbonates derived from isatins with thiocarbonyl fluoride (F2C=S) in situ generated from Zard's reagent proceeds smoothly under mild conditions, affording difluoromethylthiolated spirocyclic oxindoles in good to excellent yields. Moreover, the asymmetric variant could be realized with a modified Cinchona alkaloid, giving the desired cyclic adducts in good to excellent yields with good enantioselectivities.magnified image

Organocatalytic Enantioselective Allylic Etherification of Morita-Baylis-Hillman Carbonates and Silanols.

The organocatalytic asymmetric allylic etherification reaction of Morita-Baylis-Hillman carbonates and silanols was reported for the first time. With modified cinchona alkaloid (DHQD)2PYR as the catalyst, a series of aromatic, heterocyclic, or aliphatic Morita-Baylis-Hillman carbonates (25 examples) worked well with triphenylsilanol, affording the corresponding products in moderate to good yields (up to 98%), high regioselectivities (>20:1), and good enantioselectivities (up to 92%). When dimethylphenylsilanol was used as the nucleophile, the product was obtained in 60% yield and 87% ee.

Diastereodivergent and Enantioselective [4+2] Annulations of γ-Butenolides with Cyclic 1-Azadienes.

An asymmetric annulation reaction of γ-butenolides and cyclic 1-azadienes containing a 1,2-benzoisothiazole-1,1-dioxide motif has been studied, proceeding in a tandem Michael addition-aza-Michael addition sequence. Endo-type cycloadducts bearing fused tetracyclic skeletons were isolated in fair yields and with high enantioselectivity (up to >99% ee) under the catalysis of modified cinchona alkaloid (DHQD)2PHAL. Besides, exo-type diastereomers could be produced using β-isocupreidine (β-ICD) as the catalyst, though with moderate enantioselectivity.

Simple approach to modular chiral scaffolds: binding functional sulfur nucleophiles to Cinchona alkaloids

A series of functional modules were regio- and stereoselectively attached to the Cinchona alkaloid scaffolds. The SN2 reactions of thiolates with alkaloid mesylate and epoxide introduced metal-complexing moieties, including the heterocyclic systems of pyridine and 1,10-phenanthroline. The respective H-bond donating thiourea and salane motifs were formed in an additional step. The modified Cinchona alkaloids were tested in the metal-catalyzed Henry and Tsuji-Trost reactions.

ChemInform Abstract: Enantioselective N‐Allylic Alkylation of N‐Propargylsulfonamides with Morita—Baylis—Hillman Carbonates and Sequential Electrophilic Cyclization.

The enantioselective N-allylic alkylation of N-propargylsulfonamides with racemic Morita–Baylis–Hillman (MBH) carbonates catalyzed by modified cinchona alkaloids has been investigated. The alkylation products from MBH carbonates with a 4-methoxyphenyl group underwent ipso-iodocyclization to give optically active azaspirocyclohexadienones via electrophilic activation of alkyne group with iodine monochloride. In contrast, ortho-selective intramolecular Friedel–Crafts reaction occurred for intermediates from MBH carbonates with other electron-rich or neutral aryl or heteroaryl substitutions via the same activation strategy, delivering multifunctional 2-benzazepine frameworks in a highly enantioenriched­ form.

Asymmetric N‐Allylic Alkylation of Hydrazones with Morita–Baylis–Hillman Carbonates

AbstractThe first asymmetric N‐allylic alkylation of hydrazones with Morita‐Baylis–Hillman (MBH) carbonates catalyzed by modified Cinchona alkaloids has been developed, affording N‐substituted hydrazones in good yields with exclusive regioselectivities and excellent enantioselectivities. Subsequent transformations of the allylic alkylation products led to synthetically useful pyrazolidinones.magnified image

Synthesis of α-amino acid derivatives and peptides via enantioselective addition of masked acyl cyanides to imines.

A general, asymmetric synthesis of amino acid derivatives is reported. Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective additions to N-Boc-aldimines. The reactions are catalyzed by a modified cinchona alkaloid, which can function as a bifunctional, hydrogen bonding catalyst, and afford adducts in excellent yields (90–98%) and high enantioselectivities (up to 97.5:2.5 er). Unmasking the addition products gives acyl cyanide intermediates that are intercepted by a variety of nucleophiles to afford α-amino acid derivatives. Notably, the methodology provides an alternative method for peptide bond formation.

Enantioselective N-Allylic Alkylation of N-Propargylsulfonamides with Morita­–Baylis–Hillman Carbonates and Sequential Electrophilic Cyclization

The enantioselective <i>N</i>-allylic alkylation of <i>N</i>-propargylsulfonamides with racemic Morita–Baylis–Hillman (MBH) carbonates catalyzed by modified cinchona alkaloids has been investigated. The alkylation products from MBH carbonates with a 4-methoxyphenyl group underwent <i>ipso</i>-iodocyclization to give optically active azaspirocyclohexadienones via electrophilic activation of alkyne group with iodine monochloride. In contrast, <i>ortho</i>-selective intramolecular Friedel–Crafts reaction occurred for intermediates from MBH carbonates with other electron-rich or neutral aryl or heteroaryl substitutions via the same activation strategy, delivering multifunctional 2-benzazepine frameworks in a highly enantioenriched­ form.

ChemInform Abstract: An Asymmetric Allylic Alkylation—Smiles Rearrangement—Sulfinate Addition Sequence to Construct Chiral Cyclic Sulfones.

An asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates and β-keto sulfones was investigated by the catalysis of modified cinchona alkaloids, whose products underwent a Smiles rearrang...

An Asymmetric Allylic Alkylation–Smiles Rearrangement–Sulfinate Addition Sequence to Construct Chiral Cyclic Sulfones

An asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates and β-keto sulfones was investigated by the catalysis of modified cinchona alkaloids, whose products underwent a Smiles rearrangement-sulfinate addition cascade to furnish highly functionalized five-membered cyclic sulfones in moderate to excellent enantioselectivity and good diastereoselectivity after treatment with DBU.

Organocatalytic Asymmetric Allylic Alkylation of Morita–Baylis–Hillman Carbonates with Phosphorus Ylides: Synthesis of Chiral 3‐Substituted 2,4‐Functionalized 1,4‐Pentadienes

AbstractA highly efficient asymmetric allylic substitution of Morita–Baylis–Hillman (MBH) carbonates with phosphorus ylides under the catalysis of modified cinchona alkaloids was developed. The reaction delivered products in moderate to good yields with excellent enantioselectivities (up to 98 % ee) for a wide range of MBH carbonates. The scope of the reaction was demonstrated by the synthesis of chiral 3‐substituted 2,4‐functionalized 1,4‐pentadienes.

Enantioselective Synthesis of cis-3-Fluoropiperidin-4-ol, a Building Block for Medicinal Chemistry

The first enantioselective route to both enantiomers of cis-1-Boc-3-fluoropiperidin-4-ol, a highly prized building block for medicinal chemistry, is reported. An enantioselective fluorination is employed, taking advantage of the methodology reported by MacMillan, which uses a modified cinchona alkaloid catalyst. In studying the fluorination reaction, we have shown that the catalyst can be replaced by commercially available primary amines, including α-methylbenzylamine, with similar levels of enantioselectivity. The piperidinols are readily crystallized to obtain enantiopure material.

ChemInform Abstract: Enantioselective Michael Reaction of Nitroalkanes onto Nitroalkenes Catalyzed by Cinchona Alkaloid Derivatives.

Abstract An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the direct Michael addition of nitroalkanes onto nitroalkenes has been described. In the presence of readily modified cinchona alkaloid derivatives, nitroethane reacted well with a variety of aromatic and heterocyclic aromatic nitroalkenes to afford products with good diastereoselectivities (dr up to 72/28) and enantioselectivities (ee up to 94%). The catalyst loading can be decreased to 2 mol % without compromising the asymmetric induction or the reaction rate.