Lithium enolates acylation

The chiral lithium enolate 2 reacts with symmetrical ketones to produce /(,/i-dialkyl-/l-hydroxy-acyl complexes 3 which serve as precursors to oc,/1-unsaturated iron complexes (see Section 1.3.4.2.5.1.1.). 

The lithium enolate 2a (M = Li ) prepared from the iron propanoyl complex 1 reacts with symmetrical ketones to produce the diastercomers 3 and 4 with moderate selectivity for diastereomer 3. The yields of the aldol adducts are poor deprotonation of the substrate ketone is reported to be the dominant reaction pathway45. However, transmetalation of the lithium enolate 2a by treatment with one equivalent of copper cyanide at —40 C generates the copper enolate 2b (M = Cu ) which reacts with symmetrical ketones at — 78 °C to selectively produce diastereomer 3 in good yield. Diastereomeric ratios in excess of 92 8 are reported with efficient stereoselection requiring the addition of exactly one equivalent of copper cyanide at the transmetalation step45. Small amounts of triphcnylphosphane, a common trace impurity remaining from the preparation of these iron-acyl complexes, appear to suppress formation of the copper enolate. Thus, the starting iron complex must be carefully purified. 

Conducting the aldol reaction at temperatures below —78 "C increases the diastereoselectivity, but at the cost of reduced yields45. Transmetalation of the lithium enolate 2 a by treatment with diethylaluminum chloride generated an enolate species that provided high yields of aldol products, however, the diastereoselectivity was as low as that of the lithium species45. Pre treatment of the lithium enolate 2a with tin(II) chloride, zinc(II) chloride, or boron trifluoridc suppressed the aldol reaction and the starting iron-acyl complex was recovered. 

The a-alkoxy iron-acyl complex 5 may be deprotonated to generate the lithium enolate 6, which undergoes a highly diastereoselective aldol reaction with acetone to generate the adduct 7 as the major product. Deprotonation of acetone by 6 is believed to be a competing reaction 30% of the starting complex 5 is found in the product mixture48 40. 

The diastereoselectivity of this reaction contrasts dramatically with the generally low selectiv-ities observed for aldol reactions of lithium enolates of iron acyls. It has been suggested thal this enolate exists as a chelated species48 the major diastereomer produced is consistent with the transition state E which embodies the usual antiperiplanar enolate geometry. 

The lithium enolate of the oc-silyl-substituted iron-acyl complex 19 reacts with aldehydes, however, products of the Peterson elimination process (E)- and (Z)-22 are usually isolat-ed22- 23,36.37 for t[1js anc other preparations of a,/t-unsaturated iron-acyl complexes see Section I.3.4.2.5.I.3.). 

The reactants are usually /V-acyl derivatives. The lithium enolates form chelate structures with Z-stereochemistry at the double bond. The ring substituents then govern the preferred direction of approach. 

Studies show that the Zr-bearing bulky ligand is exclusively located in the bottom hemisphere with respect to the plane of the (Z)-enolate. The aldehyde molecule coordinates with the Zr atom and approaches from the same side, adopting a chair-like transition state. This leads to the formation of erythro-aldols (Scheme 3-9 and 23). For lithium enolate, the attack of alkyl or acyl halides in alkylation or acylation occurs directly on the top face of the enolate. 

P-Keto esters.2 In the presence of a trace of tertiary amine, an acid reacts with 1 in THF at 0° to form a 2-acyl-3,5,dioxo-l,2,4-oxadiazolidine (2). This activated form of an acid reacts with the lithium enolate of an ester in THF at - 75°... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

The reactivity of lithium enolates has been explored in a theoretical study of the isomers of C2H30Li, such as the lithium enolate, the acyl lithium, and the a-lithio enol. Imides containing a chiral 2-oxazolidine have been employed for enantioselective protonation of prochiral enolates.A degree of kinetic control of the product E/Z-enolate ratio has been reported for the lithiation of 3,3-diphenylpropiomesitylene, using lithium amides/alkyls. " °... 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

In the alkylation reactions of the chiral 3-acyl-2-oxazolidinones, deprotonation to the lithium or sodium enolate is by treatment with lithium diisopropylamide or lithium or sodium hexamethyldisilazanide in tetrahydrofuran at low temperature (usually — 78 °C). The haloalka-ne, usually in excess, is then added to the enolate solution at low temperature (usually — 78 °C) for the sodium enolates and at higher temperatures (between —78 and 0CC) for the lithium enolates. When small, less sterically demanding halides, such as iodomethane, are used the sodium enolate is usually preferred 2 24 and in these cases up to five equivalents2,6- 24,26,27 of the halide are necessary in order to obtain good yields of the alkylation products. Conventional extractive workup provides the crude product as a diastereomeric mixture (d.r. usually > 90 10) which is relatively easy to separate by silica gel chromatography and/or by recrystallization (for crystalline products). Thus, it is possible to obtain one diastereomer in very high diastereomeric purity. 

Treatment of lithium enolate species, such as 7, with a variety of metal halide species produces enolates with different reactivities in particular, diethylaluminum(IH) and copper(I) species have been found to profoundly alter stereodifferentiation in reactions of iron acyl enolates (see Section D.1.3.4.2.5.1.). It has not been established whether complex formation or discrete ti ansmetalation occurs usually, a temperature increase from — 78 °C to — 42 °C is required for maximum effect, suggesting that cation exchange is responsible. In some cases, such additives exert an influence at —78 °C13, and this has been attributed to simple Lewis acid-type interactions with the substrate instead of transmetalation of the enolate species. For simplicity, when such additives are allowed to react with enolate species at temperatures of — 42 =C and above prior to the addition of other reagents, the process shall be referred to as transmetalation. 

A synthetic route to Elaeocarpus alkaloids has been explored. Acylation of the lithium enolate (197) by the benzoyl cyanide (198) gave the diketone (199), which is the key intermediate in a previously reported synthesis of elaeocarpine (Section 3.08.8.2) (79TL1339). 

C-Acylation of the lithium enolates derived from 4-methoxybut-3-en-2-ones is achieved with acid chlorides without any significant O-acylation. A general route to pyranones results which avoids the acidic conditions frequently associated with other synthetic methods (80TL1197). Cyclization of these products, which exist in an enolic form, occurs at room temperature in benzene in the presence of a trace of trifluoroacetic acid (Scheme 135). 

Page et al. (see [298] and references therein) have shown that generally excellent stereocontrol in organic reactions can be obtained by using DITOX (1,3-dithiane-l-oxide) derivatives as chiral auxiliaries. The one-pot stereo-controlled cycloalkanone synthesis given here outlines some aspects of the chemistry worked out for efficient acylation-alkylations steps. Of note are the use of N-acyl imidazoles under mixed base (sodium hexamethyldisilazide/n-butyllithium) conditions to yield the lithium enolates of 2-acyl-l,3-dithiane-l-oxides) and the sequential alkylation-cyclization of the latter (steps (iv) and (v)). 

In a rather more unusual process, presumably involving tellurium-lithium exchange, acyl tellurides may be converted into silyl enol ethers of acyl silanes by treatment with butyl lithium and trimethylchlorosilane. In this procedure it is the Z isomer which is the predominant product (Scheme 24)100. 

In an interesting transformation, reaction of benzoyl trimethylsilane with lithium enolates derived from various methyl ketones gives rise to 1,2-cyclopropanediols, predominantly with the cis configuration, in good yields (Scheme 77). The reaction, which proceeds through addition, Brook rearrangement and cyclization, is also successful with a,/l-unsaturated acyl silanes vide infra, Section IV.D)187. 

The Claisen-type condensation reaction of cyclic vinylogous carboxylic acid triflates with lithium enolates and their analogues has provided acyclic alkynes bearing a 1,3-diketone-type moiety.19 The reaction mechanism has been proposed to proceed via a 1,2-addition of the enolate to the vinylogous acyl triflate, followed by fragmentation of the aldolate intermediate (Scheme 2). 

Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [15]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [16]. Lithium enolates derived from A-acyloxazolidinones 38, reacted readily with DTBAD to produce the hydrazide adducts 39 in excellent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by A-acylation of (S)-4-(phenylmethyl)-2-oxazoli-dinone and the lithium-Z-enolates of 38 were generated at -78 °C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17]. 

Enolate acylation and alkylation.1 The yield from acylation and alkylation of lithium ketone enolates is markedly improved by addition of dimethylzinc, which... 

Reductive acylation of enones.1 The lithium enolate generated by reduction of enones with Li/NH, is converted to a (1-keto ester by reaction with this reagent in ether (THF promotes O-acylation). 

The lithiation of an O-vinyl carbamate with rAr-BuLi followed by transmetallation with zinc bromide provides the convenient acyl anion derivative, which undergoes smooth Pd(0)-catalyzed cross-coupling reactions (Equation (24)).67 This reaction sequence has been extended to lithium enolates. The deprotonation of the aminoester with LDA followed by a transmetallation with zinc bromide in ether furnishes a zinc enolate, which readily adds to the double... 

Q Show how alkylation and acylation of enamines and lithium enolates are used Problems 22-68, 73, and 74... 

The product of acylation on oxygen is an enol ester. The tendency to attack through oxygen is most marked with reactive enolates and reactive acylating agents. The combination of a lithium enolate and an acid chloride, for example, is pretty certain to give an enol ester. 

Hydrolysis and decarboxylation in the usual way lead to keto-esters or keto-acids. Of the more common metals used to form enolates, lithium is the most likely to give good C-acylation as it> like magnesium, forms a strong O-Li bond. It is possible to acylate simple lithium enolates with enoliz-able acid chlorides,... 

This reaction worked well, as did the rest of the synthesis of pallescensin A which was first made by this route. The key step, the acylation of the lithium enolate, is interesting because it could have alkylated instead. The acid chloride is more electrophilic than the alkyl chloride in this reaction, though alkylation does occur in the next step, Notice how the lithium atom holds the molecules together during the reaction. 

It will not be possible to have a free OH group on the lactone during this step as the acid chloride would, of course, react there too. In practice, protection as a silyl ether (Chapter 24) was enSugh and the lithium enolate was then used for the acylation reaction. Aqueous ethanol work-up removed the silyl protection. 

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