Generation of chiral boron enolates by rhodium-catalyzed asymmetric 1,4-addition of 9-aryl-9-borabicyclo[3.3.1]nonanes (B-Ar-9BBN) to alpha,beta-unsaturated ketones

Asymmetric 1,4-addition of 9-phenyl-9-borabicyclo[3.3.1]nonane (2m) to 2-cyclohexenone (1a) proceeded with high enantioselectivity in toluene at 80 degrees C in the presence of 3 mol % of a rhodium catalyst generated from [Rh(OMe)(cod)]2 and (S)-binap to give a high yield of boron enolate (S)-3am, which is 98% enantiomerically pure. Reaction of the boron enolate 3am with electrophiles, methanol-d, propanal, and allyl bromide, gave the corresponding 2-substituted (3S)-3-phenylcyclohexanones with perfect regio- and diastereoselectivity.     

Palladium-catalyzed asymmetric allylic alkylation with an enamine as the nucleophilic reagent

An enamine can serve as a good nucleophile for palladium-catalyzed asymmetric allylic alkylation, avoiding the use of an unstablilized ketone enolate formed by strong bases. In the presence of a palladium complex of chiral metallocene-based phosphino-oxazoline ligands, the reaction was carried out smoothly with high catalytic activity and excellent enantioselectivity. Different distances between the two Cp rings of ferrocene and ruthenocene affected the catalytic behavior in the reaction. Furthermore, high catalytic activity and good enantioselectivity were also afforded by the ferrocene-based diphosphine ligands with only planar chirality.     

Phase-transfer-catalyzed asymmetric acylimidazole alkylation

2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at -40 degrees C with allyl and benzyl electrophiles in high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6-20 h) under mild conditions, consistent with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and transformations that proceed through an enolate intermediate.     

Decarboxylative aldol reactions of allyl beta-keto esters via heterobimetallic catalysis

Mild and selective heterobimetallic-catalyzed decarboxylative aldol reactions involving allyl beta-keto esters have been developed. The reaction is promoted by Pd(0)- and Yb(III)-DIOP complexes at room temperature and involves the in situ formation of a ketone enolate from allyl beta-keto esters followed by addition of the enolate to aldehydes. The reaction is a new example of heterobimetallic catalysis in which the optimized reaction conditions require the addition of both metals.     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

The new method for introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one and its application to chiral Wieland-Miescher type compound synthesis

The stereoselective introduction of an allyl group into the angular position of 2-(TBS-oxymethyl)-2,3,4,6,7,8-hexahydro-1-benzopyran-5-one was accomplished using Birch reduction and an enolate trapping reaction. It was determined that the allyl group was introduced via an unexpected conformation-flipped from the initially formed one. Two diastereomeric Wieland-Miescher type compounds, having the allyl group at the angular position, were synthesized as optically pure forms.     

Control of the enantioselectivity of alkylation of phenylalanine derivatives by regulation of the aggregate structure of chiral enolate intermediates

Two strategies were introduced for the control of enantioselectivity of alkylation of phenylalanine derivatives by regulation of the aggregate structure of chiral enolate intermediates. Use of amino acid-dimers, 6 and 15, was effective to minimize solvent- and electrophile-dependency of enantioselectivity of the alkylation. α-Allylation of 20 proceeded in improved selectivity of 82-88% ee under the control of aggregation of the intermediary enolate.     

A chiral ligand-mediated asymmetric addition of a lithium BHA ester enolate to an aldehyde

The asymmetric reaction of a lithium enolate generated from a BHA (2, 6-di-tert-buty-4-methoxyphenyl) propanoate was allowed to react with benzaldehyde in the presence of a diether-type chiral ligand affording the corresponding anti-aldol product in a moderate enantioselectivity. A tetradentate ligand induced better enantioselectivity albeit relative loss of anti-selectivity. A variation of lithiating amide agent affected the selectivity, indicating involvement of an amine as a component of the mixed aggregate. Absolute configuration of some of the aldol products was determined by standard transformations.     

Unexpected ambidoselectivity in crossed-aldol reactions of α-oxy aldehyde trichlorosilyl enolates

The ambido-, stereo- and enantioselectivity of the phosphoramide-promoted aldol reactions of α-oxy aldehyde trichlorosilyl enolates with benzaldehyde has been investigated. Analysis of the products from α-tert-butyldimethylsilyloxy α-deuterioacetaldehyde trichlorosilyl enolate confirmed that this 1,2-bis-silyloxyethene derivative reacted as a tert-butyldimethylsilyl enolate rather than trichlorosilyl enolate in the aldol reaction with very high ambidoselectivity. The phosphoramide-coordinated trichlorosilyl group acted as an organizing center for the aldol reaction. From the aldol process, excellent anti-diastereoselectivity could be achieved. The enantioselectivity remained moderate to low for both anti- and syn-diastereomer with a wide range of phosphoramide catalysts. α-Triisopropylsilyloxy, phenoxy and benzyloxy acetaldehyde trichlorosilyl enolates also reacted in a similar fashion with benzaldehyde to give aldol products with varying degrees of selectivities.     

Tandem Sakurai-aldol addition reactions as a route to structurally complex carbocycles

Tandem intramolecular Sakurai-aldol reactions provide a concise and highly diastereoselective route to substituted cyclohexenone derivatives. The cyclization substrates are readily obtained using olefin isomerization-Claisen rearrangement (ICR) reactions to prepare the key chiral allyl silane precursors. The Claisen reaction products are elaborated to the chiral Sakurai-aldol substrates by an efficient two-step sequence involving vinyl organometallic-aldehyde addition and oxidation of the resulting alcohol. The reaction of the resulting enones with TiCl(4) elicits a highly stereoselective allyl silane conjugate addition to produce a trichlorotitanium enolate as the reaction intermediate; intermolecular trapping of the enolate with an aldehyde provides pentasubstituted cyclohexanone derivatives in which the annulation reaction establishes four stereocenters and two new C-C bonds. A fully intramolecular variant of the Sakurai-aldol reaction that creates four stereocenters, two new C-C bonds, and establishes two new carbocyclic rings is also described.     

Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling

A chiral enolate aggregate 1 containing a lithium enolate and a chiral lithium amide was systematically investigated by various NMR techniques. (1)H and (13)C DOSY at 25 and -78 degrees C provide its solution structure, aggregation number, and formula weight. Multiple 2D (6)Li NMR techniques, such as (6)Li-(6)Li EXSY, (6)Li-(1)H HOESY, were utilized to investigate its stereochemical structure. The configuration of the enolate in complex 1 was confirmed by (6)Li-(1)H HOESY and trapping with TMS-Cl. A unique (6)Li-(1)H coupling through the Li-N-C-H network was observed. This scalar coupling was corroborated by (6)Li-(1)H HMQC, deuterium labeling experiments, and selective (1)H decoupling (6)Li NMR. The stereostructure of 1 provides a model for the origin of enantioselectivity of chiral lithium amide-induced enolate addition reactions.     

New syntheses of jasmone and 2,3-dihydfojasmone

Starting from 3-silylcyclopent-2-enone, a tandem conjugate addition—nucleophilic alkylation process was used to prepare the title compounds as well as allyl rethrone. 1,2-Dimethoxyethane was found useful in the alkylation of the enolate intermediate whereas β-silyl group facilitated the regeneration of C-C double bond.     

A ternary complex reagent for an asymmetric Michael reaction of lithium ester enolates with enoates

A lithium ester enolate was activated by both a chiral etheral ligand and a lithium amide to form a ternary complex reagent that reacted with enoates giving the corresponding Michael addition products in reasonably high enantioselectivity of up to 97% ee.     

Photocatalytic Enantioselective Hydrosulfonylation of α,β-Unsaturated Carbonyls with Sulfonyl Chlorides

This research explores the enantioselective hydrosulfonylation of various α,β-unsaturated carbonyl compounds via the use of visible light and redox-active chiral Ni-catalysis, facilitating the synthesis of enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing the reactivity between chiral metal-coordinated carbonyl compounds and moderate electrophilic sulfonyl radicals, aiming to minimize the background reactions. The success of our approach stems from two distinctive attributes: 1) the Cl-atom abstraction employed for sulfonyl radical generation from sulfonyl chlorides, and 2) the single-electron reduction to produce a key enolate radical Ni-complex. The latter process appears to enhance the feasibility of the sulfonyl radical's addition to the electron-rich enolate radical. An in-depth investigation into the reaction mechanism, supported by both experimental observations and theoretical analysis, offers insight into the intricate reaction process. Moreover, the versatility of our methodology is highlighted through its successful application in the late-stage functionalization of complex bioactive molecules, demonstrating its practicality as a strategy for producing α-chiral sulfones.     

Intermediate as catalyst: catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides

Catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides is promoted by a mesitylcopper/(R)-DTBM-Segphos precatalyst, affording γ-nitrothioamides in moderate to high syn-selectivity and excellent enantioselectivity. The intermediate Cu-thioamide enolate functions as a soft Lewis acid/hard Br?nsted base cooperative catalyst to drive the catalytic cycle efficiently under proton transfer conditions.     

Powdered KOH in DMSO: an efficient base for asymmetric cyclization via memory of chirality at ambient temperature

Enolate chemistry has been extensively used for stereoselective C-C bond formation, in which metal amide bases are frequently employed in strictly anhydrous solvents at low temperatures. However, we found that asymmetric intramolecular C-C bond formation via axially chiral enolate intermediates proceeded in up to 99% ee at 20 degrees C using powdered KOH in dry or wet DMSO as a base. The enantioselectivity was even higher than that of the corresponding reactions with potassium hexamethyldisilazide in DMF at -60 degrees C. The racemization barrier of the axially chiral enolate intermediate was estimated to be approximately 15.5 kcal/mol. On the basis of the barrier, the chiral enolate intermediate was supposed to undergo cyclization within approximately 10(-3) sec at 20 degrees C after it is generated to give the product in >or=99% ee. Thus, enolates generated with powdered KOH in DMSO were expected to be extremely reactive.     

Lewis acid-mediated selective chlorinations of silyl enolate

A new method involving efficient, widely applicable, and highly selective alpha-chlorination of simple silyl enolate with Lewis acid and an alpha,alpha-dichloro-1,3-dicarbonyl controller unit was reported. Diastereoselectivity and enantioselectivity of the reaction were investigated. High reactivity and selectivity were achieved by using alpha,alpha-dichlorinated malonic ester.     

Enantioselective and diastereoselective Tsuji-Trost allylic alkylation of lactones: an experimental and computational study

The Tsuji-Trost protocol has been successfully employed for the allylic alkylation of preformed lactone enolates. It has been demonstrated that this Pd-catalyzed reaction can be carried out in an enantio- and diastereoselective manner. The use of additives, such as LiCl, was found to be crucial for reaching high levels of product selectivity. For one particular pair of reactants, density functional theory was used to investigate the mechanism of the nucleophilic addition. Among the five pathways considered, the reaction between an (allyl)Pd(BINAP) complex and a LiCl-lithium enolate adduct is predicted to be the most likely route for C-C bond formation. LiCl plays a key role as the connecting link between the noble metal and the enolate in the kinetically favored transition state. The computed diastereoselectivity ratio is in good agreement with the experimentally observed value.     

Highly stereoselective C-allylation of an enantiopure alpha-sulfinyl thioacetamide

The alkylation of the lithium enolate of enantiopure alpha-cyclohexylsulfinyl thioacetamide 1 with allyl bromides 5 possessing an electron-withdrawing group at the vinylic position does not occur at the sulfur center - as expected in the sulfur series - but at the carbon center through conjugate addition followed by bromide elimination. The modest to excellent 1,2-asymmetric induction achieved by the alkylsulfinyl group (dr up to 100:0) is explained by an electronic model.     

Synthesis and Lewis acid catalyzed Claisen rearrangement of 2-(1,3-oxazolin-2-yl)-substituted allyl vinyl ethers

Allyl vinyl ethers containing an acceptor function in the 2-position are useful substrates for the Lewis acid-catalyzed Claisen rearrangement. The first synthesis of acyclic 2-(1,3-oxazolin-2-yl)-substituted allyl vinyl ethers is reported. The Lewis acid catalyzed Claisen rearrangement of these allyl vinyl ethers afforded the rearrangement products with low to moderate diastereo- and enantioselectivity. The catalyzed rearrangement of chiral allyl vinyl ethers was investigated. The combination of substrate- and catalyst-induced diastereoselectivity led to unexpected and unprecedented results.