In organic chemistry, the Keck asymmetric allylation is a chemical reaction that involves the nucleophilic addition of an allyl group to an aldehyde. The catalyst is a chiral complex that contains titanium as a Lewis acid. The chirality of the catalyst induces a stereoselective addition, so the secondary alcohol of the product has a predictable absolute stereochemistry based on the choice of catalyst. This name reaction is named for Gary Keck.
The Keck asymmetric allylation has many applications to the synthesis of natural products, [1] including (−)-Gloeosporone, [2] Epothilone A, [3] the CD-Subunit of spongistatins, [4] and the C10-C20 Subunit of rhizoxin A, [5] The Keck allylation has also been utilized to form substituted tetrahydropyrans enantioselectively, moieties found in products such as phorboxazole and bryostatin 1. [6]
Although the groups of E. Tagliavini[ who? ] and K. Mikami[ who? ] reported the catalysis of this reaction using a Ti(IV)–BINOL complex in the same year as the Keck group, [7] [8] Keck's publication reported higher enantio- and diastereoselectivity, and did not require the use of 4 Angstrom molecular sieves as in Mikami's procedure or an excess of BINOL as in Tagliavini's procedure. [9]
Keck's early success with stereoselectivity and the simplicity of the catalyst preparation led to many improvements in reaction design, including development of other structural analogs of BINOL, use of stoichiometric additives to enhance the reaction rate, and broadening the scope of the reaction to include substituted stannane nucleophiles.
The mechanism of this allylation is not fully known, although a cycle involving activation of the aldehyde by the bidentate BINOL-Ti complex followed by the addition of the allyl ligand to the aldehyde, removal of the tributyltin, and transmetallation to regenerate the Ti complex has been proposed. [10] [11]
Work performed by Keck and followed up by Faller and coworkers showed a positive nonlinear effect (NLE) correlating the product enantiomeric purity with the BINOL enantiomeric purity. These observations imply that a dimeric meso-chiral catalyst is less active than the homochiral dimers, leading to the observed chiral amplification. [10] [11]
Corey and coworkers established a CH-O hydrogen bonding model that accounts for the absolute stereochemistry of the transformation. [12]
The Tagliavini group, which had carried out asymmetric allylation using a similar BINOL-Ti(IV) complex, followed up early successes by synthesizing a variety of enantiopure substituted binaphthyl ligands. The most successful of these substituted binaphthyls, shown below, gave 92% product enantiomeric excess in the addition of allyltributyltin to aldehydes with a Ti(OiPr)2Cl2 metal complex. [13]
The Brenna group developed a synthesis for a binol analog, shown below,[ which? ] which can be resolved into its enantiomers quite easily and used as a chiral auxiliary for stereoselective Keck allylations, showing in some cases improved enantiomeric excesses of up to 4% over the (R)-BINOL catalyzed allylations. [14] Additionally, the developed auxiliary also showed an NLE similar to the classic BINOL, allowing enantio-impure quantities to be used.
Faller's group, whose aforementioned work helped elucidate the chiral amplification of the reaction, also developed the use of diisopropyl tartrate in a chiral poisoning strategy. Diisopropyl tartrate, racemic BINOL, Ti(OiPr)4, phenylaldehyde, and allyltributyltin were used to give enantiomeric excesses of up to 91%. [11]
Yoshida and coworkers developed a synthesis of dendritic binaphthols that serve as homogenous, easily recoverable catalyst systems, and showed that they were amenable to forming homoallylic alcohols using Keck's allylation conditions. [15]
Maruoka and Kii developed a bidentate Ti(IV) binol ligand for the allylation of aldehydes with the aim of restricting M-O bond rotation between the lewis acid and the aldehyde in order to improve enantiomeric excesses. The bidentate ligand contains two titaniums, binols, and an aromatic diamine connecting moiety, gave enantiomeric excesses of up to 99%. [16] Improved stereoselectivity is proposed to come from double activation of the carbonyl from the titaniums, a hypothesis supported by C13 NMR and IR spectroscopy studies on 2,6-γ-pyrone substrate. The most convincing evidence that the M-O rotation is restricted comes from NOE NMR studies on trans-4-methoxy-3-buten-2-one. Radiation of methoxyvinyl protons in free enone and in enone complexed with monodentate Ti(IV) show s-cis and s-trans conformations, while radiation of the enone in a bidentate Ti(IV) complex showed predominantly s-trans conformers. In 2003, this group extended the allylation strategy using this bidentate catalyst to ketones. [17]
Two key steps in the allylation reaction involve breakage of the Sn-C bond in the allyl fragment and formation of the O-Sn bond to facilitate reproduction of the Ti(IV) catalyst. Chan Mo-Yu and coworkers developed an alkylthiosilane accelerator to promote both of these steps, simultaneously increasing the reaction rate and lowering the required catalyst dosages. [18] Coupling of phenylaldehyde with allyltributyltin afforded 91% yield and 97% enantiomeric excess of homoallylic alcohol using 10 mol% of the BINOL-Ti(IV) catalyst, however addition of the alkylthiosilane and use of only 5 mol% catalyst gave 80% yield and 95% enantiomeric excess of homoallylic alcohol.
Brueckner and Weigand extended the use of this allylation chemistry to beta-substituted stannanes, including those that contain heterocycles, in 1996, exploring a variety of titanium alkoxides, premixing times, and reaction temperatures. [19] The optimal discovered conditions were 10 mol% Ti(OiPr)4 or Ti(OEt)4, 20 mol% enantiopure BINOL, with a premixing period of 2 hours, giving enantiomeric excesses of up to 99%.
In organic chemistry, the ene reaction is a chemical reaction between an alkene with an allylic hydrogen and a compound containing a multiple bond, in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position.
1,1′-Bi-2-naphthol (BINOL) is an organic compound that is often used as a ligand for transition-metal catalysed asymmetric synthesis. BINOL has axial chirality and the two enantiomers can be readily separated and are stable toward racemisation. The specific rotation of the two enantiomers is 35.5° (c = 1 in THF), with the R enantiomer being the dextrorotary one. BINOL is a precursor for another chiral ligand called BINAP. The volumetric mass density of the two enantiomers is 0.62 g cm−3.
The Corey–Itsuno reduction, also known as the Corey–Bakshi–Shibata (CBS) reduction, is a chemical reaction in which a prochiral ketone is enantioselectively reduced to produce the corresponding chiral, non-racemic alcohol. The oxazaborolidine reagent which mediates the enantioselective reduction of ketones was previously developed by the laboratory of Itsuno and thus this transformation may more properly be called the Itsuno-Corey oxazaborolidine reduction.
In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the stereoselectivity of one or more subsequent reactions. The auxiliary can then be typically recovered for future use.
The Strecker amino acid synthesis, also known simply as the Strecker synthesis, is a method for the synthesis of amino acids by the reaction of an aldehyde with cyanide in the presence of ammonia. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid. The method is used for the commercial production of racemic methionine from methional.
Asymmetric induction describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis.
The Meerwein–Ponndorf–Verley (MPV) reduction in organic chemistry is the reduction of ketones and aldehydes to their corresponding alcohols utilizing aluminium alkoxide catalysis in the presence of a sacrificial alcohol. The advantages of the MPV reduction lie in its high chemoselectivity and its use of a cheap environmentally friendly metal catalyst. MPV reductions have been described as "obsolete" owing to the development of sodium borohydride and related reagents.
In organic chemistry, the Mukaiyama aldol addition is an organic reaction and a type of aldol reaction between a silyl enol ether and an aldehyde or formate. The reaction was discovered by Teruaki Mukaiyama in 1973. His choice of reactants allows for a crossed aldol reaction between an aldehyde and a ketone, or a different aldehyde without self-condensation of the aldehyde. For this reason the reaction is used extensively in organic synthesis.
Bis(oxazoline) ligands (often abbreviated BOX ligands) are a class of privileged chiral ligands containing two oxazoline rings. They are typically C2‑symmetric and exist in a wide variety of forms; with structures based around CH2 or pyridine linkers being particularly common (often generalised BOX and PyBOX respectively). The coordination complexes of bis(oxazoline) ligands are used in asymmetric catalysis. These ligands are examples of C2-symmetric ligands.
Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogen to a target (substrate) molecule with three-dimensional spatial selectivity. Critically, this selectivity does not come from the target molecule itself, but from other reagents or catalysts present in the reaction. This allows spatial information to transfer from one molecule to the target, forming the product as a single enantiomer. The chiral information is most commonly contained in a catalyst and, in this case, the information in a single molecule of catalyst may be transferred to many substrate molecules, amplifying the amount of chiral information present. Similar processes occur in nature, where a chiral molecule like an enzyme can catalyse the introduction of a chiral centre to give a product as a single enantiomer, such as amino acids, that a cell needs to function. By imitating this process, chemists can generate many novel synthetic molecules that interact with biological systems in specific ways, leading to new pharmaceutical agents and agrochemicals. The importance of asymmetric hydrogenation in both academia and industry contributed to two of its pioneers — William Standish Knowles and Ryōji Noyori — being collectively awarded one half of the 2001 Nobel Prize in Chemistry.
Chiral Lewis acids (CLAs) are a type of Lewis acid catalyst. These acids affect the chirality of the substrate as they react with it. In such reactions, synthesis favors the formation of a specific enantiomer or diastereomer. The method is an enantioselective asymmetric synthesis reaction. Since they affect chirality, they produce optically active products from optically inactive or mixed starting materials. This type of preferential formation of one enantiomer or diastereomer over the other is formally known as asymmetric induction. In this kind of Lewis acid, the electron-accepting atom is typically a metal, such as indium, zinc, lithium, aluminium, titanium, or boron. The chiral-altering ligands employed for synthesizing these acids often have multiple Lewis basic sites that allow the formation of a ring structure involving the metal atom.
Organostannane addition reactions comprise the nucleophilic addition of an allyl-, allenyl-, or propargylstannane to an aldehyde, imine, or, in rare cases, a ketone. The reaction is widely used for carbonyl allylation.
In organic chemistry, the Baylis–Hillman, Morita–Baylis–Hillman, or MBH reaction is a carbon-carbon bond-forming reaction between an activated alkene and a carbon electrophile in the presence of a nucleophilic catalyst, such as a tertiary amine or phosphine. The product is densely functionalized, joining the alkene at the α-position to a reduced form of the electrophile.
The Tsuji–Trost reaction is a palladium-catalysed substitution reaction involving a substrate that contains a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the π-allyl complex. This allyl complex can then be attacked by a nucleophile, resulting in the substituted product.
In Lewis acid catalysis of organic reactions, a metal-based Lewis acid acts as an electron pair acceptor to increase the reactivity of a substrate. Common Lewis acid catalysts are based on main group metals such as aluminum, boron, silicon, and tin, as well as many early and late d-block metals. The metal atom forms an adduct with a lone-pair bearing electronegative atom in the substrate, such as oxygen, nitrogen, sulfur, and halogens. The complexation has partial charge-transfer character and makes the lone-pair donor effectively more electronegative, activating the substrate toward nucleophilic attack, heterolytic bond cleavage, or cycloaddition with 1,3-dienes and 1,3-dipoles.
In organic chemistry, carbonyl allylation describes methods for adding an allyl anion to an aldehyde or ketone to produce a homoallylic alcohol. The carbonyl allylation was first reported in 1876 by Alexander Zaitsev and employed an allylzinc reagent.
The Krische allylation involves the enantioselective iridium-catalyzed addition of an allyl group to an aldehyde or an alcohol, resulting in the formation of a secondary homoallylic alcohol. The mechanism of the Krische allylation involves primary alcohol dehydrogenation or, when using aldehyde reactants, hydrogen transfer from 2-propanol. Unlike other allylation methods, the Krische allylation avoids the use of preformed allyl metal reagents and enables the direct conversion of primary alcohols to secondary homoallylic alcohols.
A phosphoramidite ligand is any phosphorus-based ligand with the general formula P(OR1)(OR2)(NRR'). Chiral versions of these ligands, particularly those derived from the BINOL scaffold, are widely used in enantioselective synthesis. The application of phosphoramidites as effective monodentate ligands for transition metal catalysis was first reported by Dutch chemist Ben Feringa. The introduction of phosphoramidite ligands challenged the notion that high flexibility in the metal–ligand complex is detrimental for high stereocontrol.
In organic chemistry, the Roskamp reaction is a name reaction describing the reaction between α-diazoesters (such as ethyl diazoacetate) and aldehydes to form β-ketoesters, often utilizing various Lewis acids (such as BF3, SnCl2, and GeCl2) as catalysts. The reaction is notable for its mild reaction conditions and selectivity.
In homogeneous catalysis, C2-symmetric ligands refer to ligands that lack mirror symmetry but have C2 symmetry. Such ligands are usually bidentate and are valuable in catalysis. The C2 symmetry of ligands limits the number of possible reaction pathways and thereby increases enantioselectivity, relative to asymmetrical analogues. C2-symmetric ligands are a subset of chiral ligands. Chiral ligands, including C2-symmetric ligands, combine with metals or other groups to form chiral catalysts. These catalysts engage in enantioselective chemical synthesis, in which chirality in the catalyst yields chirality in the reaction product.