Magnesium enolates aldol reactions

Several workers have observed aldol reactions with enolates prepared by reductive removal of an o-heteroatom from a carbonyl compound. The classic example is the Reformatsky reaction, which is reviewed in Volume 2, Chapter 1.8. Dubois and coworkers have employed this method for the preparation of magnesium enolates. An important example from this study, which stimulated much of the subsequent work on aldol stereoselectivity, is shown in equation (21). 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

Aldol reactions of 1 and 2 can be used to obtain any one of the four possible stereoisomers of a,3-dihydroxy esters.3 Thus 1 reacts with aldehydes to provide (2S)-aldols, and 2 reacts to provide (2R)-aldols. The syn/anti ratio of the aldols can be controlled by the choice of the enolate counterion. Thus lithium or magnesium enolates provide mainly an/i-aldols, whereas 5yn-aldols predominate with zirconium enolates. Ethanolysis of the purified adducts yields the optically pure a,p-dihydroxy esters without epimerization with recovery of 8-phenylmenthol. 

The chelation between a Boc group and Mg(II) is often used to control the stereochemistry in aldol reactions. For instance, Donohoe and House have reported the diasteroselec-tive reductive aldol reactions of Boc-protected electron-deficient pyrroles. The key step of the synthesis is the preparation of an exocyclic magnesium enolate of Boc-protected 2-substituted pyrroles. ... 

Thioamides of secondary amines are deprotonated with isopropyhnagnesium to give (Z)-enolates. Thioamides of primary amines react with two equivalents of /-PrMgBr to afford dianions that have been shown to have the (Z)-configuration. These magnesium species are versatile intermediates in stereoselective aldol reaction (equation 50, Table 5 ... 

TABLE 5. Stereochemistry of aldol reaction of magnesium enolates derived from thioamides with aldehydes... 

The effectiveness of magnesium enolates as nucleophilic agents limits the interest of the reaction. With less substituted substrates (R = H), the aldol reaction is faster than the sily-lation. Moreover, due to solubility limitations, the authors are unable to determine whether the high thermodynamic kinetic ratio of silylenol ethers obtained accurately represents the magnesium enolate composition. Nonetheless, this method is an excellent procedure to selectively prepare the thermodynamic silylenol ether from an unsymmetrical ketone. ... 

An important reaction of silylenol ethers is their use as enolate equivalent in Mukaiyama aldol additions. An example of the synthetic utility of this reaction with a magnesium enolate as starting reagent is shown below. 

Magnesium enolates react with aldehydes and ketones to give aldol products after hydrolysis. The reaction proceeds both regio- and stereoselectively and has found many applications in the synthesis of natural products. 

Aldol reactions of magnesium enolates are frequently more diastereoselective than the corresponding reactions of lithium enolates. The aldol condensation proceeds via a cyclic transition state in agreement with the Zimmerman-Traxler chelated model . 

In addition to the structural effects due to the geometry of a substituted magnesium enolate, the stereochemistry of the reaction with a chiral aldehyde can be controlled, as described in equation 85. The aldol reaction based on the addition of magnesium enolate 56 to aldehyde 55 has been applied to the synthesis of monensin. The chiral center in the aldehyde induces the preferential approach of one diastereotopic face of the aldehyde by... 

Conseqnently, the magnesinm chelate 71 can also react as a nucleophilic donor in aldol reactions. In the chemistry involving magnesium chelates, these two aspects model their mode of action as nucleophilic partners in aldol condensations. This is exemplified in aldol condensations of y-diketones . Thus, sodium hydroxyde catalyzed cyclization of diketone 73 to give a mixtnre of 3,5,5-trimethyl-cyclopent-2-enone 74 and 3,4,4-trimethyl-cyclopent-2-enone 75 in a 2.2/1 isomeric ratio (equation 100). When treated with magnesinm methanolate, the insertion of a a-methoxy carbonyl group as control element, as in 76, allows the formation of a chelated magnesium enolate 77, and the major prodnct is now mainly the aldol 78. This latter treated with aqueous NaOH provides the trimethylcyclopent-2-enones 74 and 75 in a 1/49 ratio. 

Aldol reactions of simple amide enolates give poor stereoselection. Stimulated by the interest in /3-lactams, the stereochemistry of aldol reactions of chiral magnesium enolates of /3-lactams has been studied . The best results have been obtained with 6,6-dibromopenams 85 (equation 108). After bromine-magnesium exchange with MeMgBr,... 

Other chiral magnesium enolates derived from amides are known to react with aldehydes. For example, the aldol-type reaction of magnesium enolate of —)-trans-2-N,N-diethylacetamide-l,3-dithiolanes-5 -oxide with isobutyraldehyde affords a single diastere-omer in 82%. The relative stereochemistry of the adduct originates from a rigid transition state 87 where the oxygen atoms of the enolate and the aldehyde are coordinated to the magnesium atom. ... 

Although iV-acyloxazolidinones 88 and iV-acylthiazolidinethiones 90 lead to an anti aldol, the respective products 89 and 91 present a different anti configuration. Consequently, the corresponding derived magnesium enolates exhibit the opposite face selection in these reactions. On the basis of previous results involving enolates of various metal complexes such as boron, titanium, lithium or sodium enolates, the (Z)-metal enolate... 

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... 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

A nickel hydride complex, NiHCl(diphenylphosphinoethane), catalyses the tandem isomerization-aldolization reaction of allylic alcohols with aldehydes.156 The atom- (g) efficient process proceeds at or below ambient temperature with low catalyst loading, and works well even for bulky aldehydes. Magnesium bromide acts as a co-catalyst, and mechanistic investigations suggest that a free enol is formed, which then adds to the aldehyde in a hydroxyl-carbonyl-ene -type reaction. 

Silyl enol ethers react with aldehydes in the presence of chiral boranes or other additives " to give aldols with good asymmetric induction (see the Mukaiyama aldol reaction in 16-35). Chiral boron enolates have been used. Since both new stereogenic centers are formed enantioselectively, this kind of process is called double asymmetric synthesis Where both the enolate derivative and substrate were achiral, carrying out the reaction in the presence of an optically active boron compound ° or a diamine coordinated with a tin compound ° gives the aldol product with excellent enantioselectivity for one stereoisomer. Formation of the magnesium enolate anion of a chiral amide, adds to aldehydes to give the alcohol enantioselectively. 

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