Enantioselective Allylation Research Articles

ChemInform Abstract: Indium‐Mediated Stereoselective Allylation

AbstractReview: 55 refs.

Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes

The widely applicable TRIP phosphoric acid catalyst has been immobilized on polystyrene using a copolymerization-based strategy. The resin (PS-TRIP) has proven to be highly active and enantioselective in the asymmetric allylboration of aldehydes. Moreover, it has shown to be extremely robust, as it can be reused for 18 times, after which it still retained its activity. Lastly, to further prove the benefits of the immobilization, a continuous flow experiment spanning 28 h has been carried out with very high yields and ee’s.

Extremely Active Organocatalysts Enable a Highly Enantioselective Addition of Allyltrimethylsilane to Aldehydes.

The enantioselective allylation of aldehydes to form homoallylic alcohols is one of the most frequently used carbon-carbon bond-forming reaction in chemical synthesis and, for several decades, has been a testing ground for new asymmetric methodology. However, a general and highly enantioselective catalytic addition of the inexpensive, nontoxic, air- and moisture-stable allyltrimethylsilane to aldehydes, the Hosomi-Sakurai reaction, has remained elusive. Reported herein is the design and synthesis of a highly acidic imidodiphosphorimidate motif (IDPi), which enables this transformation, thus converting various aldehydes with aromatic and aliphatic groups at catalyst loadings ranging from 0.05 to 2.0 mol % with excellent enantioselectivities. Our rationally constructed catalysts feature a highly tunable active site, and selectively process small substrates, thus promising utility in various other challenging chemical reactions.

Indium-Mediated Stereoselective Allylation

Stereoselective indium-mediated organic reactions have enjoyed tremendous growth in the last 25 years. This is in part due to the insensitivity of allylindium to moisture, affording facile and practical reaction conditions coupled with outstanding functional group tolerance and minimal side reactions. Despite the plethora of articles about allylindium, there is much yet to be discovered and exploited for efficient and sustainable synthesis. In this Account, we describe indium-mediated synthetic methods for the preparation of chiral amines with the aim to present a balance of practical method development, novel asymmetric chemistry, and mechanistic understanding that impact multiple chemical and materials science disciplines. In 2005, we demonstrated the indium-mediated allylation of chiral hydrazones with complete diastereoselectivity (>99:1) and quantitative yields. Further, we revealed the first example of enantioselective indium-mediated allylation of hydrazones using catalytic (R)-3,3'-bis(trifluoromethyl)-BINOL ligands to afford homoallylic amines with high enantioselectivity. The use of enantiopure perfluoroalkylsulfonate BINOLs greatly improved the indium-mediated allylation of N-acylhydrazones with exquisite enantiocontrol (99% yield, 99% ee). This laboratory has also investigated indium-mediated asymmetric intramolecular cyclization in the presence of amino acid additives to deliver biologically relevant chromanes with excellent diastereoselectivity (dr >99:1). The effect of amino acid additives (N-Boc-glycine) was further investigated during the indium-mediated allylation of isatins with allyl bromide to yield homoallylic alcohols in excellent yields in a short time with a wide range of functional group tolerance. Critical mechanistic insight was gained, and evidence suggests that the additive plays two roles: (1) to increase the rate of formation of allylindium from allyl bromide and In(0) and (2) to increase the nucleophilicity of the allylindium reagent, probably through disruption of aggregates and coordination to the metal. We recently reported the palladium-catalyzed umpolung allylation of hydrazones with allyl acetates in the presence of indium(I) iodide (InI) with excellent diastereoselectivity (up to 99:1). The conversion was found to be inversely proportional to the phosphine concentration, providing insight into the mechanism of the critical redox transmetalation process that has implications for other Pd-catalyzed umpolung-type allylation processes. A detailed overview of the work in our lab is presented with the intention of stimulating further research interest in organoindium chemistry and its application in organic synthesis.

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.

Enantioselective Allyl–Allyl Coupling between Boronates and Phosphates

Enantioselective Allyl–Allyl Coupling between Boronates and Phosphates

ChemInform Abstract: Imidazolylpyridine‐In(OTf)3 Catalyzed Enantioselective Allylation of Ketimines Derived from Isatins.

An enantioselective In(OTf)3-catalyzed allylation of ketimines derived from isatins in the presence of an imidazolylpyridine ligand is described. The reaction proceeded smoothly under mild conditions and resulted in 3-allyl 3-aminooxindoles with good yields and moderate to excellent enantioselectivities (up to 97% ee).

Iridium-Catalyzed Regio- and Enantioselective Allylic Substitution of Trisubstituted Allylic Electrophiles.

The first Ir-catalyzed enantioselective allylation of trisubstituted allylic electrophiles has been developed. Through modification of the leaving group of allylic electrophiles, we found that trisubstituted allylic phosphates are suitable electrophiles for asymmetric allylation. The reaction of allylic phosphates with enol silanes derived from dioxinones gave allylated products in good yields with high enantioselectivities.

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Trisubstituted Allylic Electrophiles

AbstractThe first Ir‐catalyzed enantioselective allylation of trisubstituted allylic electrophiles has been developed. Through modification of the leaving group of allylic electrophiles, we found that trisubstituted allylic phosphates are suitable electrophiles for asymmetric allylation. The reaction of allylic phosphates with enol silanes derived from dioxinones gave allylated products in good yields with high enantioselectivities.

Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups.

Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates1. However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown2. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable, as the resulting products would be subjected to further modifications; such reactions, especially when dienoates contain two equally substituted olefins, are scarce3 and are confined to reactions promoted by a phosphine–copper (with alkyl Grignard4,5, dialkylzinc or trialkylaluminum compounds6,7), a diene–iridium (with arylboroxines)8,9, and a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)10. 1,6-conjugate additions are otherwise limited to substrates where there is full substitution at C411. It is not clear why certain catalysts favor bond formation at C6, and – while there are a small number of catalytic enantioselective conjugate allyl additions12,13,14,15 – related 1,6-additions and processes involving a propargyl unit are non-existent. In this manuscript, we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenylboron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 percent yield, >98 percent diastereo- (for allyl additions) and 99:1 enantiomeric ratio. Mechanistic details, including the origins of high site- (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, have been elucidated by means of density functional theory (DFT) calculations.

ChemInform Abstract: Enantioselective Allylic Substitution of Morita—Baylis—Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines.

AbstractAir‐stable chiral ferrocenylphosphines are synthesized and utilized in the asymmetric allylic substitution of Morita—Baylis—Hillman adducts with phthalimide under mild reaction conditions.

ChemInform Abstract: Iridium‐Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α‐Alkoxy Ketones.

AbstractAllylic substitution reactions with acyclic α‐alkoxy ketones are catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile.

Copper‐Catalyzed Enantioselective Allyl–Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N‐Heterocyclic Carbene Chiral Ligand

AbstractCopper‐catalyzed enantioselective allyl–allyl coupling between allylboronates and either Z‐acyclic or cyclic allylic phosphates using a new chiral N‐heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional SN2′‐type regioselectivities and high enantioselectivities to deliver chiral 1,5‐diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position.

Copper-Catalyzed Enantioselective Allyl-Allyl Coupling between Allylic Boronates and Phosphates with a Phenol/N-Heterocyclic Carbene Chiral Ligand.

Copper-catalyzed enantioselective allyl-allyl coupling between allylboronates and either Z-acyclic or cyclic allylic phosphates using a new chiral N-heterocyclic carbene ligand, bearing a phenolic hydroxy, is reported. This reaction occurs with exceptional SN 2'-type regioselectivities and high enantioselectivities to deliver chiral 1,5-diene derivatives with a tertiary stereogenic center at the allylic/homoallylic position.

Enantioselective Allylations of Selected α,β,γ,δ-Unsaturated Aldehydes by Axially Chiral N,N’-dioxides. Synthesis of the Left-hand Part of Papulacandin D

Enantioselective Allylations of Selected α,β,γ,δ-Unsaturated Aldehydes by Axially Chiral N,N’-dioxides. Synthesis of the Left-hand Part of Papulacandin D

Enantioselective Allylic C−H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis

AbstractThe enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)‐catalyzed allylic C−H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide‐oxazoline (ArSOX) ligand. The allylic C−H oxidation reaction proceeds with the broadest scope and highest levels of asymmetric induction reported to date (avg. 92 % ee, 13 examples with greater than 90 % ee).

Enantioselective Allylic C-H Oxidation of Terminal Olefins to Isochromans by Palladium(II)/Chiral Sulfoxide Catalysis.

The enantioselective synthesis of isochroman motifs has been accomplished by palladium(II)-catalyzed allylic C-H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C-H oxidation reaction proceeds with the broadest scope and highest levels of asymmetric induction reported to date (avg. 92 % ee, 13 examples with greater than 90 % ee).

ChemInform Abstract: Palladium‐Catalyzed Enantioselective Allylic Alkylation of Trifluoromethyl Group Substituted Racemic and Acyclic Unsymmetrical 1,3‐Disubstituted Allylic Esters with Malonate Anions.

AbstractThis Pd‐catalyzed dynamic kinetic asymmetric allylic alkylation proceeds with high yields and good to excellent enantioselectivity.

ChemInform Abstract: Catalytic SN2′‐ and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis.

AbstractThe utility of this method is demonstrated in the synthesis of compound (XI) which is a precursor in the synthesis of cytotoxic natural product rhopaloic acid A (XII).

ChemInform Abstract: Recent Progress in Copper‐Catalyzed Asymmetric Allylic Substitution Reactions Using Organoboron Nucleophiles

AbstractReview: [29 refs.