STEREOSELECTIVE ENOLATE REACTIONS

It is also important to note that several factors influence both the stereoselectivity of hydrogen exchange and enolate formation in base-promoted reactions. Houk, Ando and co-workers found that differing conju-gative stabilization by CH p-orbital overlap does not directly influence stereoselectivity.205 Steric effects only dominate is exceptionally crowded transition structures, but torsional strain involving vicinal bonds contributes significantly to the stereoselectivity of all cases studied. 

L Alkylation. If the aldol condensation reaction that produces 330 could be controlled, one diast-ereomer might be formed in preference to the other, making the reaction diastereoselective. There are two essential factors that control diastereoselectivity in this reaction the face from which the two reagents approach and the relative orientation of the two molecules. 

The enolate alkylation process with simple aldehydes and ketones does not generally lend itself to enan-tioselective control, due to the planar nature of the enolate Jt system.206 inspection of 331 shows that the si-re face (face a) has no more steric hindrance than the re-si face (face b). When this enolate reacts with iodo-methane, therefore, no facial selectivity is anticipated and the product will be racemic. In general, enolate alkylation reactions produce chiral, racemic products. The reaction can be diastereoselective, however, when substituents attached to the molecule provide facial bias. In general, enolate alkylation proceeds by approach 

Diastereoselection in the Aldol Condensation. In addition to the alkylation reaction, enolates react with other carbonyl compounds to give aldol or Claisen products, as discussed in previous sections. An aldol condensation with the enolate of 1-phenyl-1-propanone and benzaldehyde generates two new stereocenters and gives two racemic diastereomers (four stereoisomers). These two diastereomers are the racemic anti diastereomer (340 and 343) and the racemic syn diastereomer (341 and 342). Diastereoselectivity in this reaction is dependent on the reaction conditions and the enolate and aldehyde partners, and this section will explore the origins of that diastereoselection. 

Heathcock et al. described the process that formed diastereomers in the aldol condensation, from precursors that do not contain a chiral center, as simple diastereoselectivity.209,210 Naming protocols to describe the diastereomers produced in the aldol condensation include the erythro/threo nomenclature, as well as the syn/anti nomenclature was discussed in Section I.4.B. Using this latter convention, diastereomers 340 and 343 were designated as anti and diastereomers 341 and 342 were designated as syn. 

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However, diastereoselective transformations like this are not to be discussed within this monograph, as they do not fulfill the criteria of asymmetric synthesis, according to Marckwald s definition (in today s language) this would mean [...] those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation [35]. Thus, diastereoselective conversions not included for that reason in this book are, for example, aldol additions, Mannich reactions, and Michael additions of enolates to ketones, imines, and cx,P-unsaturated carbonyl compounds, respectively, with any chiral skeleton. For such stereoselective enolate reactions that are not asymmetric syntheses, the reader is referred to the literature, which treated this topic in a comprehensive manner [36]. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

In contrast, highly stereoselective aldol reactions are feasible when the boron etiolates of the mandelic acid derived ketones (/ )- and (5,)-l- t,r -butyldimethylsiloxy-l-cyclohexyl-2-butanone react with aldehydes33. When these ketones are treated with dialkylboryl triflate, there is exclusive formation of the (Z)-enolates. Subsequent addition to aldehydes leads to the formation of the iyn-adducts whose ratio is 100 1 in optimized cases. 

Lewis acid catalysis has been used to promote stepwise [2 + 2] cycloaddition of silyl enol ethers and unsaturated esters.178 The best catalyst is (C2H5)2A1C1 and polyfluoroalkyl esters give the highest stereoselectivity. The reactions give the more stable trans products. 

In the presence of zinc chloride, stereoselective aldol reactions can be carried out. The aldol reaction with the lithium enolate of /-butyl malonate and various a-alkoxy aldehydes gave anti-l,2-diols in high yields, and 2-trityloxypropanal yielded the syn-l,2-diol under the same conditions.633 Stoichiometric amounts of zinc chloride contribute to the formation of aminoni-tropyridines by direct amination of nitropyridines with methoxyamine under basic conditions.634 Zinc chloride can also be used as a radical initiator.635... 

Based on a similar literature method,116 stereoselective coupling reactions between various 3-acetoxy-4-alkyl-/3-lactams and in situ-generated titanium enolates of cyclohexanone117 or propiophenone derivatives were developed, yielding the corresponding a,/3-disubstituted /3-lactams. 

Usually, (Z)-boron enolates can be prepared by treating /V-acyl oxazolidones with di-K-butylboron triflate and triethylamine in CH2CI2 at 78°C, and the enolate then prepared can easily undergo aldol reaction at this temperature to give a, vy -aldol product with more than 99% diastereoselectivity (Scheme 3-4). In this example, the boron counterion plays an important role in the stereoselective aldol reaction. Triethylamine is more effective than di-wo-propylethyl amine in the enolization step. Changing boron to lithium leads to a drop in stereoselectivity. 

The (Z)-silyl enol ether (4) of 1 can be obtained with high stereoselectivity by reaction of 3 with C6H5(CH3)2SiLi. 

For a stereoselective dialkylzinc reaction with a phosphinoylimine, see Addition to Organometallics below a resolution via a Schiff base is described under Enolates. 

The lithium enolate of di-i-butyl malonate undergoes a stereoselective aldol reaction with Qf-alkoxyaldehydes to give anft-l,2-diol derivatives in the case of the highly hindered 2-trityloxypropanal, the stereochemistry is reversed. 

Since the formation of optically active, dioxolanone-based di-enolates was not successful, a consecutive alkylation strategy was developed for a short synthesis of (-)-wikstromol (ent-3) from (-)-malic acid (99) (Scheme 25). The first alkylation reaction was analogous to that reported for the enantioselective total synthesis of (-)-meridinol (97). In order to avoid a reduction/re-oxidation sequence and an almost unselective second alkylation, two disadvantages of the synthesis of meridinol (97) [55], we planned to use a different strategy for the second alkylation. Therefore, we have focused our strategy on two stereoselective alkylation reactions, one of dialkyl malates and one of a dioxolanone prepared thereof. Both alkylation reactions were previously described by Seebach and coworker [56, 63, 64]. The... 

An example of such a rearrangement, in which the intermediate enolate has been further treated with alkylation agents29, is shown for enolate 12. The intermediate enolate can also undergo an aldol reaction. Thus, trapping the enolate with benzaldehyde provides an indication that the Z-enolate is the predominating species29. Further systematic studies are needed in order to assess the applicability of this method of stereoselective enolate formation. However, the potential for the use of this method in asymmetric synthesis appears to be good29. 

Rotation is hindered in the enolate. Thus, if the a-substituent R1 4= R2, the enolate can exist in two forms, the syn- and anti-forms (enolates 2 and 3, respectively, if R2 has higher priority than R1). Attack of an electrophile on either face of the enolates, 2 or 3, leads to a mixture of the alkylated amides, 4 and 5. If R1 and R2 and the A-substituents R3 and R4 are all achiral, the two alkylated amides will be mirror images and thus a racemate results. If, however, any of the R substituents are chiral, enolate 2 will give a certain ratio of alkylated amide 4/5, whereas enolate 3 will give a different, usually inverted, ratio. Thus, for the successful design of stereoselective alkylation reactions of chiral amide enolates it is of prime importance to control the formation of the enolate so that one of the possible syn- or anti-isomers is produced in large excess over the other,... 

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 ... 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

Organoaluminum reagents, 202 1,1,1-Trifluoroacetone, 323 Trityllithium, 338 Zinc chloride, 349 Stereoselective aldol reactions With boron enolates Boron trichloride, 43 Chlorodimethoxyborane, 73 9-(Phenylseleno)-9-borabicyclo-[3.3.1]nonane, 245 With silyl enol ethers... 

D. A. Evans in Asymmetric Synthesis, Ed. J. D. Morrison, Academic Press, New York (1984), Vol 3, Chpt 1 (stereoselective alkylation reactions of chiral metal enolates)... 

The stereoselectivity in reactions of P-alkylthio-a,(3-enones with organocuprates is dependent upon both the solvent and bulk of the ligand in the cuprate. Ether solutions favor inversion, while THF solutions favor retention (Scheme 19). It was proposed that in coordinating solvents such as THF, a more reactive enolate is formed, which eliminates before rotation occurs, thereby giving retention of configuration.108... 

Chiral 2-sulfinylcyclohexanones react with lithium alkyl acetates (i.e. lithium ester enolates) to produce alcohols with four contiguous chiral centres.57 This stereoselective aldol reaction is proposed to depend upon tricoordination by lithium of the enolate, sulfinyl, and carbonyl oxygens of the substrates. 

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in Asymmetric Syn-... 

The preparation of the /3-haloenones starting materials sometimes requires acidic reaction conditions. In view of the synthetic potential of the vinylic tellurides (Section 9.13.8.2) associated with the above-commented stereoselectivity, enol phosphates are employed instead as starting materials for the preparation of vinylic tellurides, since enol phosphates can be prepared under very mild basic conditions. 

To achieve a stereoselective aldol reaction that does not depend on the structural type of the reacting carbonyl compounds, many efforts have been made to use boron enolates. Based on early studies by Mukaiyama et al.8a and Fenzl and K0ster,8b in 1979, Masamune and others reported a highly diastereoselective aldol reaction involving dialkylboron enolates (enol borinates)9... 

Oppolzer et al. completed an asymmetric synthesis of (-)-denticulatin A (48) by using a syn-aldol methodology as a key feature18 (Scheme 2.1r). The diethyl-boron enolate of N-propionyIbomanesultam (46-ent) obtained from diethylboron triflate and Hunig s base underwent a highly stereoselective aldol reaction with the mes o-dialdchydc 49 to furnish the lactols 50 in 74% yield as a 2 1 epimeric mixture. When the lactols 50 were treated with 1, 2-ethanedithiol in the presence... 

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