Enolates stereoselective reactions

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Transfer of chirality in aldol reactions has been attempted using / -allenyl ester enolates. These ambident nucleophiles have an axis of chirality, and such compounds have been less utilized in stereoselective reactions. They are prepared by transmetallation of the... 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

K. Krohn, Stereoselective Reactions of Cyclic Enolates , in Organic Synthesis Highlights (J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. ReiBig, Eds.), VCH, Weinheim, New York, etc., 1991, 9-13. 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

Stereoselective trans a-hydroxylation of (5)-dihydro-5-(t-butyldiphenylsiloxymethyl)-2(3/f)-furanone can be realized in good yield by enolization and reaction with the Oxodiperox-ymolybdenum(pyridine)(hexamethylphosphoric triamide) complex (MoOPH) (eq 10). Appropriate manipulation of the resulting trans-hydroxylactone provides 1,3-polyols typified by (18), as well as tetrahydropyran (19) which is a key intermediate in mevinic acid syntheses. ... 

The first stereoselective reaction is surprising as it may appear that the initial alkylation decides " stereochemistry. But that is not the case as you will see if you draw the mechanism. The esn enolate is very easily formed as it is stabilized by the pyridine ring and the nitrile as well as by irt ester. Even a weakish base like carbonate is good enough. 

A stereoselective reaction leads to the exclusive or predominant formation of one of several possible stereoisomeric products. Thus, one reaction pathway from a given substrate is favored over the other (as in nucleophilic additions to cyclic ketones or alkylations of enolate ions). 

Stereoselective acyclic enolization. This reaction can sometimes be achieved by conjugate reduction of acyclic a,p-enones by lithium tri-sec-butylborohydride (1). When an enone reacts with 1 mainly by 1,2-reduction Li/NH3 can be used for conjugate reduction. In at least one case reduction with 1 is more stereoselective than that with Li/NH3. The stereoselectivity in general can be correlated with conformational preferences of enones. ... 

Bernard , A., Capelli, A. M., Comotti, A., Gennari, C., Gardner, M., Goodman, J. M., Paterson, I. Origins of stereoselectivity in chiral boron enolate aldol reactions a computational study using transition state modeling. Tetrahedron 1991, 47, 3471-3484. 

Evans, D. A., Bartroli, J. Stereoselective reactions of chiral enolates. Application to the synthesis of (+)-Prelog-Djerassi lactonic acid. Tetrahedron Lett. 1982, 23, 807-810. 

Myers et al. found that silyl enolates derived from amides undergo a facile non-catalyzed aldol addition to aldehydes at or below ambient temperature [90]. In particular, the use of cyclic silyl enolate 27, derived from (S)-prolinol propionamide, realizes high levels of diastereoface-selection and simple diastereoselection (anti selectivity) (Scheme 10.27). It has been proposed that this non-catalyzed highly stereoselective reaction proceeds via attack of an aldehyde on 27 to produce a trigonal bipyramidal intermediate 29 in which the aldehyde is apically bound 29 then turns to another isomer 30 by pseudorotation and 30 is then converted into 28 through a six-membered boat-like transition state (rate-determining step). 

The enantioselective hetero-Diels-Alder reactions of a,p-unsaturated acylphosphonates with enol ethers catalyzed by Cu(II)bzT(oxazoline) complexes have been investigated in depth. It was found that Cu(II)bA(oxazoline) complexes activate a,p-unsaturated acylphosphonates to the extent that they undergo facile cycloaddition reactions at low temperature with electron-rich alkenes. For example, dimethyl ( )-l-oxo-2-butenylphosphonate reacts with ethyl vinyl ether in the presence of Cu[(S,5)-t-Bu-box] (OTf)2 complex (10 mol% catalyst) to generate the cycloadduct in 89% yield (Scheme 7.86) with exceptional stereoselectivity (endo/exo = 99/1, 99% ee). Cyclic enol ethers also undergo stereoselective reactions with dimethyl ( )-l-oxo-2-butenylphosphonate. It specifically reacts with 2,3-dihydrofuran in the presence of Cu[(5,5)-t-Bu-box] (OTf)2 to deliver the bicyclic enolphosphonate. Of particular merit is the fact that a large variety of p.y-unsaturated acylphosphonates may be tolerated with no loss in selectivity for the derived cycloadducts. ... 

Some kinds of metal enolate also give highly stereoselective reactions in the same sense whatever the geometry of the enolate. At first sight the reactions of zirconium enolates seem like lithium enolates. Using the pyrrolidine amide 38 as an example, we get the Z-enolate 39 only and this gives syn aldol products 40 with aldehydes.13... 

Reaction with electrophiles can be by SE2 reaction 232 as in the last example but the other end of the double bond can react if it is part of, for example, an enolate 233. Reaction of 234 is an example of the latter and highly stereoselective. 

Hydroxylation of sodium and potassium enolates side reaction with lithium Substrate controlled stereoselectivity asymmetric hydroxylation Asymmetric hydroxylation with camphor sultam derivatives Asymmetric synthesis of tetracycline precursors Synthesis of a calcium channel opening drug Asymmetric synthesis ofbuproprion Summary... 

The Li—F chelation is also useful for stereoselective reactions. In particular, chelation between lithium of enolates and a fluorine of a trifluoromethyl group results in conformational fixation of substrates, leading to markedly enhanced stereoselection. This concept has often been employed to achieve stereocontrol in fluorinated enolate chemistry. Morisawa reported Li—F chelation-controlled stereoselective a-hydroxylation of enolate of 40 [22]. The oxidant approaches from the less hindered side of the Li—F chelated enolate intermediate (41), affording anti-alcohol (42) exclusively (Scheme 3.11). The syn-alcohol (45) was prepared by NaBlrh reduction of ketoester (43) via a reaction course predicted by Felkin-Anh s model (44). 

An interesting and highly stereoselective reaction of dimethoxy cyclopropane derivative 81 with some aromatic N-tosyl imines was recently described by Saigo and coworkers [41] (Scheme 16). In the presence of TiCl4, compound 81 condenses with N-sulfonyl imines to stereoselectively produce lactams 84 and 85, with the cis isomer being the predominant product. It is likely that the dimethoxy cyclopropane initially opens to zwitterionic ester enolate 82, which adds to the imine to yield intermediate 83. The rationale presented for the stereoselectivity in condensation of enolate 82 with the imines is similar to that described for the reactions in Schemes 14 and 15, cf. Fig. (1). 

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