Enolate equivalents synthesis

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

Tiic synthesis of enone (34) requires an aldol condensation between acetone and KCHO this may not give a good yield as RCHO may prefer to condense with Itself if it has enolisable protons. The alternative disconnection (33b) avoids this problem as we can use acetoacetatc for the synthon (34) and a specific enol equivalent for (35),... 

One published synthesis uses a propargyl bromide for (21) and an activating group to provide a specific enol equivalent (22),... 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Enamines are the stable products of a similar reaction between secondary amines (such as pyrrolidine or morpholine) and aldehydes and ketones.218 These vinylamines are reactive reagents of value in synthesis they function as specific enol equivalents of carbonyl compounds, readily undergoing alkylation and acylation processes (e.g. Section 5.9.2, p. 632). 

Figure 12.25 shows how acetals can be brominated electrophihcally because of the (weakly) acidic reaction conditions. Proper acidity and electrophihcity is ensured by the use of pyri-dinium tribromide (B). This reagent is produced from pyridinium hydrobromide and one equivalent of bromine. Pyridinium tribromide is acidic enough to cleave the acetal A into the enol ether G. This cleavage succeeds by way of an El elimination like the one encountered in Figure 9.32 as an enol ether synthesis. The enol ether G reacts with the tribromide ion via the bromine-containing oxocarbenium ion H and the protonated acetal D to form the finally isolated neutral bromoacetal C. (The reaction can be conducted despite the unfavorable equilibrium between the acetal A and the enol ether G, since G continuously reacts and is thus eliminated from the equilibrium.)... 

The use of silyl enol ethers can be illustrated in a synthesis of manicone, a conjugated enone that ants use to leave a trail to a food source. It can be made by an aldol reaction between the pentan-3-one (as the enol component) and 2-methylbutanal (as the electrophile). Both partners are enolizable so we shall need to form a specific enol equivalent from the ketone. The silyl enol ether works well. 

When the Wittig reaction was introduced (Chapter 14) we saw it simply as an alkene synthesis. Now if we look at one group of Wittig reagents, those derived from a-halo-carbonyl compounds, we can see that they behave as specific enol equivalents in making unsaturated carbonyl compounds. 

The product of a conjugate addition of an enolate or enol equivalent to an a,(3-unsaturated carbonyl compound will necessarily be a dicarbonyl compound or an equivalent derivative. As the carbonyl group occupies such a central position in synthesis it will come as no surprise that these intermediates, with two carbonyl groups, are very widely used. 

For the synthesis of the pyrrolizidine fragment (2), we identified maleic anhydride (5, 7 /kg), aminobutyric acid (6, 120 /kg) and trienal 7 as readily available starting materials. In the most ambitious disconnection, the racemic pyrrolizidine carboxylic acid 4a, could be assembled, in principle, in a single step from 4-aminobutyric acid (6) and maleic anhydride (5). A subsequent kinetic resolution via oxa-Michael addition would then generate an enantiomerically enriched enolate equivalent, which could in turn add to the aldehyde 3. However,... 

Condensation of 1,2-dielectrophiles with a component that serves as a l,3-C,0-nucleophile is the underlying principle of a number of improved methods for furan synthesis. Bis-silyl enol ethers are suitable enol equivalents for the condensation with dielectrophiles to produce furans. Langer and co-workers have made use of this concept in the synthesis of annulated furans with l-chloro-2,2-dimethoxyethane as electrophile <2005EJ02074>. In a stepwise reaction comprising TMS triflate-assisted aldol reaction and cyclization with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, 3-methoxy exomethylene tetrahydrofurans are obtained, which finally yield the furan reaction products upon treatment with trifluoroacetic acid (Scheme 18). 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

For the complementary synthesis of a-substituted-a-amino acids via a chiral glycine enolate equivalent see 4-t-Butoxycarbonyl-5,6-diphenyl-2,5,5,6-tetrahydro-4H-oxazin-2-one. 

Silyl enol ethers are versatile reagents in organic synthesis [83]. They are used as isol-able enolate equivalents and many useful reactions have been developed using silyl enol ethers [83]. As a new approach to exploit an efficient method for combinatorial synthesis [84], silyl enol ethers were successfully immobilized on to a polymer. Polymer-supported silyl enol ethers (PSSEEs) were prepared according to Sch. 10 [85]. In aldol reactions of PSSEEs with aldehydes, it was again found that Sc(OTf)3 was an efficient catalyst [86]. An example of the preparation of a 1,3-diol library by use of PSSEEs is shown in Sch. 11. In all cases, the reactions proceeded smoothly to afford the corresponding 1,3-diols in good yields. 1,3-Diols are successfully cleaved from the... 

Much interest lies in the use of dihydro-1,3-oxazines (190) as enolate equivalents, since, if an alkyl group is carried at C-2, these compounds may be deprotonated and the anions formed reacted with numerous types of electrophiles. Reduction of the imine bond of the products (191), is then conveniently effected by treatment with sodium borohydride. The tetrahydrooxazines (192) which are formed may then be ring opened by hydrolysis with aqueous acid (Scheme 15). This topic and its utility in synthesis has been well reviewed. - ... 

The Patemo-Buchl reaction of furan and various aldehydes was shown to be a highly stereoselective photochemical version of the aldol reaction by S.L. Schreiber and co-workers in which the furan serves as an enolate equivalent. This strategy was applied to the total synthesis of the antifungal metabolite (+)-avenaciolide. The photocycloaddition of nonanal with excess furan proceeded in nearly quantitative yield, and the two out of the three required stereocenters were created in a single step. The photocycloadduct was first hydrogenated then hydrolyzed under acidic conditions. 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

Specific enol equivalents (e. g. (3-keto esters) and umpolung (e. g., with cyanide or acetylide ions as acyl anion equivalents) have of course been used in synthesis for many years. What is new is the recognition of their role, as a result of the disconnec-... 

Once the a-PhS-ketone 102 has been used as a specific enol equivalent, the PhS group can be removed from 103 in a variety of ways. Reduction, as with aluminium amalgam, simply replaces PhS by H so that the ketone 104 is formed. This approach has been used in the synthesis of dihydrojasmone59) and PGE2 derivatives65). 

Aldol reactions with specific enol equivalents Contrast with equilibrium methods Aldols with Lewis acid catalysis silyl enol ethers Application to the synthesis of gingerol Reaction at O or C Silylation, Acylation and Alkylation Naked enolates... 

The most important method6 for the regioselective synthesis of less substituted enolates is kinetic enolate formation with strong irreversible bases (LDA etc). Since the lithium enolate7 20 can be converted into the silyl enol ether8 21 directly without isolation, we have access to the two most valuable specific enol equivalents for the less substituted isomer. Alkylation of the lithium enolate of 23 goes more than 99% on the less substituted side.9... 

The same strategy, but with the opposite polarity, along with other enone approaches is illustrated by the bicyclic enone 84 needed for the synthesis of the terpene cadinene. Aldol disconnection gives the 1,5-diketone 85 which we expect to make by a Michael addition.18 Hence we require a specific enol equivalent of cyclohexanone to add to the enone 86, and we have rediscovered the Robinson annelation.19... 

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