Enolate intermediate, alkylation

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

Ketones can be oxidatively carbonylated at the a-carbon via enol intermediates using PdCl2 as the catalyst and Q1CI2 as oxidant [122], The initially formed carbonylation products correspond to a-chlorination and a-alkoxycarbonylation. Under the reaction conditions, these compounds undergo further transformations involving C - C cleavage eventually leading to a mixture of esters and an alkyl chloride or (in the case of cyclic ketones) to a diester and a chloroester (Schemes 20-21). 

Prior to the advent of triphenylphosphine-stabilized CuH [6a, b, 13], Tsuda and Saegusa described use of five mole percent MeCu/DIBAL in THE/HMPA to effect hydroalumination of conjugated ketones and esters [26]. The likely aluminium enolate intermediate could be quenched with water or TMSCl, or alkylated/acylated with various electrophiles (such as Mel, allyl bromide, etc. Scheme 5.5). More... 

Quenching this reaction with deuteriomethanol gave 2-methylcycloheptanone having deuterium at the 2-position (199 E = D) in 75% yield with 95% deuterium incorporation. Aldehydes and benzoyl chloride gave the desired products in 60-70% yields. Alkylation of the enolate intermediate (198) was successfully carried out with alkyl halides in the presence of HMPA in good yields. The reaction with ethyl chloroformate and chlorotri-ethylsilane gave enol carbonate (200) and sUyl enol ether (201) in 74 and 75% yield, respectively. 

Recently, Maruoka described the novel dual function catalyst 26 bearing hydroxyl groups which were incorporated to allow hydrogen bonding to the enolate intermediate. Indeed, 26 was found to catalyze enone epoxidation with 89-99% tt [67]. Interestingly - and unlike some other systems - alkyl substitution is tolerated (Scheme 12.14). 

S)-Methyl-3-(benzoylamino)butanoate (S)-72 is also available by enzymatic resolution with pig liver esterase. Alkylation and amination were run on the racemic compounds. One example of electrophilic amination is reported starting from rac-72 which is doubly deprotonated with LDA at low temperature (-60 °C to -45 °C). The enolate intermediate adopts an (E) configuration. After treatment at -70 °C with DTBAD (1.2 equiv.) in THF, the product 73 is obtained with 96% yield and an excellent diastereoselectivity de > 99 % in favor of the anri-diastereomer (Scheme 34). The absolute configuration of the created stereogenic center was assigned by chemical correlation with the known anti-2,3-diaminobutanoic acid. 

The ability of Sml2 to reduce alkyl halides has been exploited in a number of carbon carbon bond-forming reactions. Radicals generated from the reduction of alkyl halides can be trapped by alkenes in cyclisation reactions to form carbocyclic and heterocyclic rings (see Chapter 5, Section 5.3), and the alkyl-samarium intermediates can be used in intermolecular and intramolecular Barbier and Grignard reactions (see Chapter 5, Section 5.4). The reduction of ot-halocarbonyl compounds with Sml2 gives rise to Sm(III) enolates that can be exploited in Reformatsky reactions (Chapter 5, Section 5.5) and are discussed in Section 4.5. 

The key step is the alkylation of the enolate intermediate. F.nolates in five-menibered rings are almost flat and the incoming alkyl halide prefers the less hindered face away from the recently added group R. The example below shows that, if both new groups have double bonds in their chains, it is easier to add a vinyl group as the nucleophile and an allyl group as an electrophile. 

The 5-alkyl cyclohexenone that we have chosen as our example gives the best results. The mechanism suggests that the enolate intermediate is protonated on the top face (axial addition again) though we cannot tell this. But, if we carry out a tandem reaction with the enolate trapped by a different electrophile, the product is again that of axial attack. 

Pyridines (and quinolines, isoquinolines) react with electron-deficient alkynes via N-alkylation and then intramolecular nucleophilic addition to an -position. Thus, for example, DMAD reacts with isoquinoline in the presence of ethyl bromopyruvate to yield pyrrole[2,l- ]isoquinolines in excellent yields (Scheme 44) <2006TL6037>. A zwitterionic mechanism is proposed, and implies an enolate intermediate with a final spontaneous oxidation. 

Two explanations have been suggested for this anomalous result83,84. Huffman and coworkers84 have proposed that the 2,2-disubstituted cyclohexanone (38) is derived directly from a 2,6-disubstituted enolate intermediate by simultaneous alkylation at C2 and dealkylation at C6. This is in effect a S 2 mechanism for which there is no precedent in enamine chemistry (Scheme 24). The basis for this suggestion is the anomalous solvent-dependent annulation of 2-substituted cyclohexanone enamines with methyl vinyl ketone (MVK) and the assumption that direct C-alkylation of a tetrasubstituted enamine is improbable for it is known that there is considerably less overlap of the unshared electrons on nitrogen with the n system of the double bond in this isomer relative to the more stable trisubstituted isomer, thereby greatly decreasing the rate of alkylation . 

Treatment of 23 with potassium hydride in the presence of an alkyl halide and 18-crown-6 in fact gave optically active a-alkylated products 24 in 48% to nearly 73% ee in the absence of any additional chiral source (Table 3.1).17 Thus chirality of optically active 23 was memorized in the enolate intermediate during its alkylation. The stereochemical course of a-methylation and ethylation was inversion. 

The potassium enolate generated from 23 is regarded as an enantiomeric atropisomer. Recently non-biaryl atropisomers have been receiving more attention in asymmetric synthesis.19 Most of them employ atropisomers that are configurationally stable at room temperature, while attention in this chapter is focused on asymmetric reactions that proceed via chiral nonracemic enolate intermediates that can exist only in a limited time. An application of configurationally stable atropisomeric amide to a chiral auxiliary for stereoselective alkylation has been reported by Simpkins and co-workers (Scheme 3.10).20... 

Figure 3.5. Determination of racemization barrier of the enolate generated from 40 and KHMDS. ee° The ee value of 41 obtained by the reaction of the enolate immediately after its generation (t = 5 min) from 40 with methyl iodide, ee1 The ee value of 41 obtained by treatment of 40 with KHMDS for the time indicated, followed by addition of methyl iodide. 0.25 mmol of 40 was employed for each run. Reactions were quenched 30 minutes after the addition of methyl iodide in order to minimize racemization of the enolate intermediate during alkylation ee° = 80% (t = 5 min), ee1=3° 111111 = 79%, 1=90 111111 = 76%, eet=m = 74%, eet=42° = 63%, eet=12° = 56%, 1=1440 111111 = 37%.

Several V- IJ<>c-A-MOM-a-am ino acid derivatives undergo a-methylation in 78% to nearly 93% ee with retention of the configuration upon treatment with KHMDS followed by methyl iodide at —78°C. The substituents of the nitrogen are essential for control of the stereochemistry. How much is the stereochemical course of the reaction affected by an additional chiral center at C(3) of substrates a-Alkylation of A -lioc-A-MOM-L-isoleucine derivative 61 and its C(2)-epimer, D-a/fo-isoleucine derivative 62, were investigated (Scheme 3.16). If the chirality at C(2) is completely lost with formation of the enolate, a-methylation of either 61 or 62 should give a mixture of 63 and 64 with an identical diastereomeric composition via common enolate intermediate K. On the other hand, if the chirality of C(2) is memorized in enolate intermediates, 61 and 62 should give products with independent diastereomeric compositions via diastereomeric enolate intermediates. 

The stereochemical course of a-alkylation of both L-isoleucine and D-allo-isoleucine derivatives 61 and 62 is controlled predominantly by the chiral axis in the enolate intermediate, whereas the adjacent chiral center C(3) has little effect. 

Photocyclization of A -alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic /ra r-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(/>-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(/ )-butenyl)benzo[ ]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>. 

Use of trimethylsilyl triflate to bring about Piunmeier rearrangement requires the presence of a base such as a tertiary amine (vide supra equations 15 and 26). In some instances, involving attempts to alkylate Pummerer intermediates with silyl enol ethers under such conditions, the base has been found to compete as a nucleophile. In the absence of the silyl enol ether, amine addition can be very efficient. For example, treatment of methallyl phenyl sulfoxide with diisopropylethylamine and trimethylsilyl inflate in dichloromethane (equation 29) at 0 C yields the ammonium triflate indicated in 91% yield. Other tertiary amines which undergo this reaction include niethylamine and Af,Af-diethyltrimethylsiI-amine. In the latter case with allyl phenyl sulfoxide as the substrate and a mildly acidic wotk-up, the Mannich derivative shown in equation (30) can be obtained in 90% yield. ... 

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