Chiral enolate nucleophile

The asymmetric alkylation of a carbonyl group is one of the most commonly used chirality transfer reactions. The chirality of a substrate can be transferred to the newly formed asymmetric carbon atom through this process. In surveying chiral enolate systems as a class of nucleophile, three general subdivisions can be made in such asymmetric nucleophilic addition reactions intra-annular, extra-annular, and chelation enforced intra-annular. 

An interesting class of chiral enolates are allenyl enolates. These ambident nucleophiles bear an axis of chirality. Krause and coworkers have found that an axis to center chirality transfer takes place in the aldol reaction of chiral magnesium allenyl enolate with pivalic aldehyde . The aldol reaction proceeds with good diastereofacial selectivity if... 

France S, Shah MH, Weatherwax A, Wack H, Roth JP, Lectka T (2(X)5) Bifunctioneil Lewis acid-nucleophile-based asymmetric catalysis mechanistic evidence for imine activation working in tandem with chiral enolate formation in the synthesis of p-lacttuns. J Am Chem Soc 127 1206-1215... 

Chemistry of the Tricyclic Diterpenoids.— The conversion of virescenol A (66 R = OH) into virescenol B (66 R = H) was complicated by the ease of 2,19-ether formation. In the event the transformation was achieved through hydro-genolysis of the keto-furan (67). The chirality of nucleophilic reactions at the C-4 axial aldehydes and methyl ketones has been examined in the podocarpane series. The reaction of some ring B enol-acetates with thallium(l) acetate and iodine has been studied.lodination at the 6a-position is followed by elimination to form a/8-unsaturated ketones. 

Unfortunately, the hydrazino esters or amides required inconveniently high pressures for their hydrogenolysis (500 psi Schemes 8.25a and b). An improvement involved the direct azidation of the same enolates using arylazide derivatives, which were found to undergo reactions with enolate nucleophiles to provide a C-sulfonyltriazene intermediate which could be decomposed to the a-azido ester (Scheme 8.25c) [110]. Alternatively, azides may be obtained by enolate bromination followed by Sn2 azide displacement note that these techniques are stereochemically complementary. Similar chemistry has also been accomplished using 10-suIfonamidoisobomyl chiral auxiliaries (Scheme 8.25d) [111]. 

Two approaches have been studied to access non-racemic products a chiral nucleophile and a chiral auxiliary. In an approach based on Pearson s earUer work with dienyliron and dienemolybdenum complexes [79],Miles used a chiral enolate derived from AT-acyloxazolidinones in a reaction with a prochiral Mn(arene)(CO)3+ complex to give a 3.5 1 mixture of chiral q -dienylmanganese... 

A unique inversion on the theme of trapping an electrophile with enolate nucleophile has been reported by Krishnan and Stoltz who have installed all-carbon quaternary centers at oxindoles, e.g., 42, in racemic fashion through the treatment of electrophilic 3-halooxindoles with nucleophilic malonates, e.g., 40-41, using DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) for the deprotonation step (Scheme 11) [28]. An asymmetric variation of the chemistry in Scheme 11 has been reported by the same group who constructed enantioeiuiched oxindoles using catalytic Cu(ll)-Lewis acid and a chiral bis(oxazoline) ligand [29]. 

Similarly, the reaction of an achiral aldehyde with a chiral enolate leads to some degree of diastereofacial selectivity and the two diastereomeric products are not produced in equal amounts. Further enhancement to the selectivity is possible using a chiral aldehyde with a chiral enolate. When both the nucleophile and the electrophile contain a chiral centre then double stereodifferentiation (or double asymmetric induction) can occur. Most of the studies in these areas use chiral, non-racemic enolates, which are discussed in the next section. 

Carbon-carbon bond forming reactions between carbanionic nucleophiles like enolates or deprotonated nitroalkanes and electron deficient alkenes and alkynes belong to the oldest and most versatile transformations known today (225-229). Moreover, stereoselective variants have proven to possess an enormous potential in the syntheses of complex molecules as already exemplified in Sect. 2.4. Whereas the applications depicted in this previous section utilized nucleophiles activated by enamine formation with a chiral secondary amine catalyst to achieve these highly selective C-C bond formations, the present discussirai will focus on the addition of carbon nucleophiles to iminium-activated Michael acceptors. Herein traditional Michael additions using e.g. enolate nucleophiles will be described whereas the use of aromatic Michael donors with iminium-activated acceptors in Friedel-Crafts type reactions will be discussed separately subsequently. 

The aldol reaction, the reaction of an enolate nucleophile with a carbonyl electrophile to give a P-hydroxy carbonyl product, has the potential to form two new chirality centers. It is possible to both predict and control the stereochemical relationship between a group on the alpha carbon and the newly formed hydroxyl group on the beta carbon. Since this relationship depends on the stereochemistry of the enolate involved, formation of the enolate must first be discussed. 

The aldol reaction is an important carbon-carbon bond formation reaction. The general concept of the reaction involves the nucleophilic addition of a ketone enolate to an aldehyde to form a P-hydroxy ketone, or aldol , a structural unit found in many naturally occurring molecules and pharmaceuticals. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. The Evans aldol reaction performs a diasteroselective aldol transformation using an Evans s acyl oxazolidinone (also known as Evans chiral auxiliary), a chiral carbonyl compound that creates a temporary chiral enolate for the aldol addition. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed. ... 

Mukaiyama variant of the Michael reaction and Michael additions of 1,3-diketones to 2-oxo-3-butenoate esters. However, these examples have always involved activation of bidentate electrophiles by Cu(II) followed by the addition of a weak nucleophile to the resultant complex. The attempts to employ bis(oxazoline)copper(II) complexes to catalyze a classical Michael reaction with p-ketoesters and monodentate enones are precedented however, racemic products were obtained in such cases. Interestingly, the Michael reaction developed in our studies is most likely to proceed via reversed activation (Scheme 11). Thus, we proposed that Cu(II) complex H chelates the enol form of p-ketoester 12a, and the resultant chiral enol complex 22 undergoes addition to electrophile (5) to provide 23. It should be noted that the precise mechanism of this reaction and particularly the step for the addition of 22 to 5 to provide 23 are yet to be investigated. 

The first catalytic, asymmetric synthesis of /3-lactams from ketenes and imines with useful selectivity was reported by Lectka, who used cinchona alkaloids [99]. The underlying principle in the development of such processes is the recognition that the optically active amine catalyst undergoes addition to the ketene to provide a chiral enolate, which then adds to the imine. The intermediate chiral zwitterion undergoes ring-closure, producing the /3-lac-tam. The cinchona alkaloid 111 has served admirably as a nucleophilic amine catalyst, furnishing adducts such as 112 with excellent enantio- and diastereoselectivity (99 1 dr, 99% ee, Equation 8) [31, 32, 99, 100]. 

An interesting example from carbohydrate chemistry is the boron trifluoride-diethyl ether complex catalyzed nucleophilic addition of silyl enol ethers to chiral imines (from n-glyceralde-hyde or D-serinal)22. This reaction yields unsaturated y-butyrolactones with predominantly the D-arabino configuration (and almost complete Cram-type erythro selectivity). 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

Among the peculiar features of 2-bromoamides there are the following i) possibility of substitution at the tertiary C-Br (RCO2H, RR NH, or a saccharide, as the nucleophiles) ii) chiral stability and stereochemical control at the secondary C-Br atom (RR NH, ROH or a saccharide as the nucleophiles) iii) the presence of bromine allows cyclic voltammetry and electroreduction at controlled potential both of starting compounds and relevant intermediates iv) the Ca polarity can be reversed upon electroreduction, and the resulting Ca enolate forms a C-C bond (CO2 as the electrophile). 

The mechanism of these reactions is usually Sn2 with inversion taking place at a chiral RX, though there is strong evidence that an SET mechanism is involved in certain cases, ° especially where the nucleophile is an a-nitro carbanion and/or the substrate contains a nitro or cyano group. Tertiary alkyl groups can be introduced by an SnI mechanism if the ZCH2Z compound (not the enolate ion) is treated with a tertiary carbocation generated in situ from an alcohol or alkyl halide and BF3 or AlCla, or with a tertiary alkyl perchlorate. ... 

Stereochemical Control by the Aldehyde. A chiral center in an aldehyde can influence the direction of approach by an enolate or other nucleophile. This facial selectivity is in addition to the simple syn, anti diastereoselectivity so that if either the aldehyde or enolate contains a stereocenter, four stereoisomers are possible. There are four possible chairlike TSs, of which two lead to syn product from the Z-enolate and two to anti product from the A-enolate. The two members of each pair differ in the facial approach to the aldehyde and give products of opposite configuration at both of the newly formed stereocenters. If the substituted aldehyde is racemic, the enantiomeric products will be formed, making a total of eight stereoisomers possible. 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

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