Stereoselective aldol condensations via alkenyloxy dialkoxyboranes : mechanistic and stereochemical details

A detailed investigation of the enolization of ketones with ethylenechloroboronate ( ECB ) in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The enolization with ECB- DPEA system was found to be regioselective except for the case of butanone. The stereochemistry of the enolates derived from ethyl ketones was defined as Z on the basis of ¹H-NMR comparison to the Z enolates obtained by a stereodefined route. A mechanistic model for the enolization is proposed to explain the enolization selectivity. E enolates were found to be more reactive than the Z enolates. The product aldol stereochemistry ( syn ) was correlated to the enolate geometry via a chairlike transition state ( Z enolates ) or via a boatlike transition state ( E enolates ).     

Sequential hydroformylation/aldol reactions: versatile and controllable access to functionalised carbocycles from unsaturated carbonyl compounds

Three different modes of hydroformylation/aldol reaction sequences involving either acid-catalysed aldol reactions, Mukaiyama aldol addition of pre-formed enolsilanes or aldol addition of in situ generated boron enolates can be applied to unsaturated ketones and ketoesters to afford the corresponding carbocyclic aldol adducts in good yields proceeding through the intermediate activated ketoaldehydes. In selected cases, complimentary, synthetically useful diastereoselectivities were observed in the products.     

The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Palladium(II)‐Catalyzed Dehydroboration via Generation of Boron Enolates

The Pd^II‐catalyzed dehydroboration of boron enolates generated from ketones and 9‐iodo‐9‐borabicyclo[3.3.1]nonane was achieved, providing a synthetically versatile protocol from ketones to α,β‐unsaturated ketones. The Pd^II compound employed in this reaction worked catalytically in the presence of Cu(OAc)₂. The high trans‐selectivity of the olefinic moiety was observed. Aryl halide moieties (‐Br and ‐Cl) remained intact for this reaction in spite of the presence of a Pd species. An ester substrate could also be applied when a stoichiometric amount of Pd^II was used. The crossover reactions using boron and silyl enolates revealed that the oxidation reaction is much faster than the Saegusa‐Ito reaction.     

Diastereoselective Aldol Addition Using Boron Trichloride or Alkoxydichloroborane

Under carefully controlled conditions, boron trichloride or alkoxydichloroborane/ethyldiisopropylamine in CH₂Cl₂ can be used to effect diastereoselective aldol additions of ethyl ketones to saturated, α, β-unsaturated, or aromatic aldehydes. The C? C bond formation takes place with relative topicity ul (‘syn,’ configuration of the aldols), in selectivities ranging from 90 to 99% ds (Tables 1–3). Mechanistic aspects of the reaction are discussed.     

Addition of kinetic boron enolates generated from β-alkoxy methyl ketones to aldehydes. Density functional theory calculations on the transition structures

Herein we report that good to excellent levels of 1,5-anti stereoinduction are obtained in boron enolate aldol reactions of 1,2-syn β-alkoxy methyl ketones with achiral aldehydes, when the β-alkoxy protecting group is part of a benzylidene acetal. We have also investigated the effects of the ligands on boron, the α-, β-, and γ-substituents and the β-alkoxy protecting group on the boron enolates, using density functional theory (B3LYP) and Møller-Plesset perturbation theory (MP2) calculations.     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-oxygenated methyl ketones

This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of beta-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the beta-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.     

Threo-selective aldol condensations of lithium enolates in the presence of trialkylboranes

The reaction of preformed lithium enolates in the presence of trialkylboranes, such as Et₂B and n-Bu₃B, with aldehydes leads to product mixtures rich in the more stable threo aldol.     

One-pot synthesis of 1,5-diketones catalyzed by barium isopropoxide

A tandem cross-coupling reaction of aryl methyl ketones with aromatic aldehydes has been accomplished employing barium isopropoxide as a catalyst, in which barium enolates are generated and then three consecutive reactions (aldol reaction/β-elimination/conjugate addition) occur; this one-pot procedure is a convenient method to obtain symmetrical 1,5-diketones in good yields. In some cases, addition of iso-propanol is effective in improving the chemical yield.     

Stereocontrolled addition of boron enolates to trans α,β-aziridine aldehydes. A new route to anti-1,2-amino alcohols

A study of the addition of boron enolates of methyl ketones to trans α,β-aziridine aldehydes is reported. The reaction proceeds with excellent anti stereoselectivity furnishing functionalized products, capable of other controlled transformations, some of which are described.     

Diastereoselective aldol reactions of enolates generated from vicinally substituted trimethylsilylmethyl cyclopropyl ketones

[reaction: see text] Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions. The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diastereoselectivity of the reaction with aldehydes depends on the nature of the Lewis acid used. The resulting aldol product is easily converted into a substituted tetrahydrofuran derivative.     

Reversibility in the boron-mediated ketone-ketone aldol reaction

The boron-mediated ketone-ketone aldol reaction is demonstrated, through 1H NMR studies, to be reversible, in contrast to the strictly irreversible aldol reactions of boron enolates with aldehydes.     

The dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat: asymmetric synthesis of α-vinyl-β-hydroxycarboxylic acid derivatives and conversion to α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products)

The synthesis of α-vinyl-β-hydroxyesters and α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) via the dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat is described. High levels of syn-diastereoselectivity (up to >98% de) are observed for the dienolate aldol reaction with boron enolates, generated either directly with Bu₂BOTf or by transmetalation of the potassium enolate with B-bromocatecholborane. Cleavage of the resultant syn-aldol products from the auxiliary gives α-vinyl-β-hydroxyesters in >98% de and >98% ee. Subsequent isomerisation of the double bond into conjugation provides α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) in high diastereo- and enantiopurity (≥91:9 [(E):(Z)] and >98% ee).     

Asymmetric aldol reactions using chiral CF3-Oxazolidines (Fox) as chiral auxiliary

The aldol reactions of amide enolates derived from a trifluoromethylated oxazolidine (Fox) chiral auxiliary occur in good yields with a moderate anti diastereoselectivity (Li and Na enolates) to a high syn diastereoselectivity (boron enolate). After removal, the Fox chiral auxiliary is very conveniently and efficiently recovered in basic conditions.     

A syn‐Selective Aza‐Aldol Reaction of Boron Aza‐Enolates Generated from N‐Sulfonyl‐1,2,3‐Triazoles and 9‐BBN‐H

A syn‐selective aza‐aldol reaction of boron aza‐enolates, generated from N‐sulfonyl‐1,2,3‐triazoles and 9‐BBN‐H, is reported. It provides a sequential one‐pot procedure for the stereoselective construction of 1,3‐amino alcohols, having contiguous stereocenters, starting from terminal alkynes.     

Indium-catalyzed coupling reaction between silyl enolates and alkyl chlorides or alkyl ethers

The coupling reactions of alkyl chlorides with silyl enolates catalyzed by InBr₃, and the coupling reactions of alkyl ethers with silyl enolates catalyzed by the combined Lewis acid of InBr₃/Me₃SiBr are described. In both reaction systems, various types of silyl enolates were used to give corresponding α-alkylated esters, ketones, carboxylic acids, amides, thioesters, and aldehydes.     

Mechanism of the double aldol reaction: the first spectroscopic characterization of a carbon-bound boron enolate derived from carboxylic esters

The novel doubly borylated enolate is identified as an intermediate of the double aldol reaction of acetate esters. As a precursor to the formation of the doubly borylated enolate, carbon-bound boron enolates of carboxylic esters are spectroscopically characterized for the first time. When 2,6-diisopropylphenyl acetate (10d) is treated with c-Hex(2)BOTf (1.3 equiv) and triethylamine (1.5 equiv) in CDCl(3), the corresponding mono-enolate is formed as a mixture of oxygen- (11d) and carbon-bound (12d) forms in 71% and 20% yields, respectively. The structures of these enolates have been unambiguously determined by NMR spectroscopy. Investigation of the enolization of a series of substituted aryl acetates shows that the steric factor of the acetate affects the degree of the mono-enolate (as a mixture of oxygen- and carbon-bound enolates) and the doubly borylated enolate formation. Studies also revealed that oxygen- and carbon-bound boron enolates exist as equilibrium mixtures and that a proton transfer process occurs between oxygen- and carbon-bound enolates. The doubly borylated enolate formation is general for a variety of carbonyl compounds. Besides acetate esters, carbonyl containing compounds, such as acetic acid, dimethylacetamide, methoxyacetone, and 3-acetyl-2-oxazolidinone, also produce the doubly borylated enolates when treated with c-Hex(2)BOTf (2.5 equiv) and triethylamine (3.0 equiv). A plausible pathway of the double aldol reaction involving a carbon-bound boron enolate as a key intermediate is proposed.     

Asymmetric acylation of carboxamides having -2,5-bis(methoxymethoxymethyl)pyrrolidine moiety as a chiral auxiliary and stereoselective reduction of the resulting 2-alkyl-3-oxoamides

-2,5-Bis(methoxymethoxymethyl)pyrrolidine proved to be an excellent chiral auxiliary for the asymmetric acylation of the corresponding carboxamide enolates and the stereoselective Zn(BH₄)₂ reduction of the resulting 2-alkyl-3-oxo amides provided a useful alternative to asymmetric aldol reaction.     

New chiral bis(diphenylphospholane) ligands: design, synthesis, and application to catalytic enantioselective aldol reaction to ketones

New chiral bidentate diphenylphospholanes were designed targeting a catalytic enantioselective aldol reaction to ketones. Ligands 5l and 5m having cis-2-butenyl and cyclopropyl groups at the linker part, respectively, were identified as effective chiral ligands for a CuF-catalyzed enantioselective aldol reaction to ketones. Catalysts prepared from CuF·3PPh₃·2EtOH and these ligands produced ketone aldol products with up to 66% ee, which is promising particularly for this extremely difficult and important catalytic enantioselective carbon-carbon bond forming reaction. The enantioselectivity was strongly dependent on the linker structure. Construction of a deep chiral pocket around the copper metal with stable bidentate chelation is the key to meaningful enantioinduction.     

Synthesis of (E)-1-Propenyl Ketones from Carboxylic Esters and Carboxamides by Use of Mixed Organolithium-Magnesium Reagents. Synthesis of α-Damascone, β-Damascone,and β-Damascenone

The novel reagents formed by combination of allylmagnesium chloride and a strong non-nucleophilic lithium base (LiNR₂) convert non- or slowly enolizable carboxylic esters or carboxamides into 2-propenyl ketones which are protected from further reaction by their in situ conversion into enolates. This modified Grignard reaction is applied to efficient syntheses of α-damascone, β-damascone, β-damascenone, and various other (E)-1-propenyl ketones.