Palladium-catalyzed regio-, diastereo-, and enantioselective benzylic allylation of 2-substituted pyridines.
ABSTRACT: We report a new method for the highly regio-, diastereo-, and enantioselective palladium-catalyzed allylic alkylation of 2-substituted pyridines that allows for the formation of homoallylic stereocenters containing alkyl, aryl, heteroaryl, and nitrogen substituents. When the reaction is conducted with asymmetric acyclic electrophiles, both linear and branched products may be obtained exclusively by selecting the appropriate regioisomeric starting material and ligand, an example of the "memory effect." Deuterium-labeling studies reveal that though no such phenomenon occurs with racemic cyclic electrophiles, the chiral ligand employed reacts kinetically faster with the enantiomer of the substrate for which it is "matched" and yet eventually converts all "mismatched" substrate to product.
Project description:Borontrifluoride etherate (BF3·OEt2) can be efficiently used for the synthesis of dihydropyrans from triethylsilyl homoallylic alcohols and aldehydes in good yields. The reaction is highly diastereo- and regio-selective.
Project description:Catalytic Asymmetric allylation of aldehydes with functionalized allylic reagents represents an important process in synthetic organic chemistry because the resulting chiral homoallylic alcohols are valuable building blocks in diverse research fields. Despite the obvious advantages of allyl halides as allylation reagent under Barbier-type conditions, catalytic asymmetric version using functionalized allyl halides remains largely underdeveloped. Here, we addressed this issue by employing a chromium-catalysis system. The use of readily available allyl bromides with ? substitutions including trimethylsilyl, fluorinated methyl and phenylthio groups provided an efficient and convenient method to introduce those privileged functionalities into homoallylic alcohols. Good yields, high anti-diastereo- and excellent enantioselectivities were achieved under mild reaction conditions.
Project description:A highly diastereo- and enantioselective protocol for the hydroallylation of 1,1- and 1,2-disubstituted cyclopropenes has been developed utilizing an in situ formed copper hydride. A variety of allyl electrophiles could be utilized yielding a diverse range of trisubstituted cyclopropanes. Finally a preliminary enantioselective variant could be established employing a recently described P-stereogenic xantphos derivative as ligand.
Project description:Chiral ruthenium(II) complexes modified by Josiphos ligands catalyze the reaction of alkynes with primary alcohols to form homoallylic alcohols with excellent control of regio-, diastereo-, and enantioselectivity. These processes represent the first examples of enantioselective carbonyl allylation using alkynes as allylmetal equivalents.
Project description:The first examples of diastereo- and enantioselective carbonyl ?-(cyclopropyl)allylation are reported. Under the conditions of iridium catalyzed transfer hydrogenation using the chiral precatalyst (R)-Ir-I modified by SEGPHOS, carbonyl ?-(cyclopropyl)allylation may be achieved with equal facility from alcohol or aldehyde oxidation levels. This methodology provides a conduit to hitherto inaccessible inaccessible enantiomerically enriched cyclopropane-containing architectures.
Project description:Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, ( R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.
Project description:meso-Cyclopropyl carbaldehydes are treated in the presence of an organocatalyst with sulfenyl and selenyl chlorides to afford 1,3-chlorochalcogenated products. The transformation is achieved by a merged iminium-enamine activation. The enantioselective desymmetrization reaction, leading to three adjacent stereocenters, furnished the target products in complete regioselectivity and moderate to high diastereo- and enantioselectivities (d.r. up to 15:1 and e.r. up to 93:7).
Project description:A highly regio-, diastereo-, and enantioselective allylic alkylation reaction mediated by a chiral molybdenum catalyst has been developed as a novel entry into synthetically versatile 3-alkyl-3-aryloxindoles. Extremely bulky nucleophiles were employed to form a quaternary center and an adjacent tertiary center asymmetrically concurrently. The regio- and diastereoselectivity of the reaction is dependent upon the steric and electronic nature of the nucleophiles to an unusual degree. A reaction mechanism based on the bonding modes of molybdenum enolate complexes was discussed.
Project description:Catalytic discrimination between inequivalent formyl groups was achieved using an aniline-type acid-base catalyst for the regio-, diastereo-, and enantioselective intramolecular cross-aldol reactions of enolizable dials. Although l-proline gave a mixture of the regio- and stereoisomeric products in the presence of an N-containing 1,6-dial, the aniline-type catalyst afforded anti-3,4-disubstituted pyrrolidine in high regio-, and stereoselectivity beyond the background reaction, which led to the regioisomeric 2,3-disubstituted products. The mild reactivity of the aniline-type amine facilitated catalytic discrimination between the inequivalent formyl groups. Kinetic isotope effect studies and reductive amination experiments suggested that the regioselectivity was controlled under the enamine-forming steps.
Project description:A highly chemo-, diastereo- and enantioselective catalytic method that efficiently combines a silyl hydride, vinyl-B(pin) (pin=pinacolato) and (E)-1,2-disubstituted allylic phosphates is introduced. Reactions, best promoted by a Cu-based complex with a chiral sulfonate-containing N-heterocyclic carbene, are broadly applicable. Aryl-, heteroaryl-, alkenyl-, alkynyl- and alkyl-substituted allylic phosphates may thus be converted to the corresponding homoallylic boronates and then alcohols (after C-B bond oxidation) in 46-91?% yield and in up to >98?% SN 2':SN 2 ratio, 96:4 diastereomeric ratio and 98:2 enantiomeric ratio. The reasons why an NHC-Cu catalyst is uniquely effective (vs. the corresponding phosphine systems) and the basis for different trends in stereoselectivity are provided with the aid of DFT calculations.