Lithium enolates complex’ aldol reactions

For catalytic asymmetric aldol-type reactions, the transformation of the methylene compounds to a silyl enolate or a silyl ketene acetal was at one time necessary. Recently, the aldol reaction of aldehydes with non-modified ketones was realized by use of the lanthanum-Li3-trisf(/ )-bi-naphthoxidej catalyst 22 [18]. According to the proposed catalytic cycle, after abstraction of an a-proton from the ketone, the reaction between the lithium-enolate complex and the aldehyde... 

A powerful variation of the iron acetyl enolate aldol reaction utilizes the cnolate of complex 8 which bears a (pentafluorophenyl)diphenylphosphane ligand in place of the more usual triphenylphosphane47. The enolate species 9. prepared by treatment of 8 with lithium diiso-propylamide, reacts at — 78 °C with benzaldehyde to produce the aldol adduct 10 with a d.r. of 98.5 1.5. 

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. 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

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). 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

Reaction of aliphatic aldehydes with alkali acetylides in liquid ammonia gives the carbinols in very small amounts, even when the aldehyde is added to a strongly cooled solution of lithium acetylide. The predominant reaction presumably is formation of the enolate and the aldol condensation product As shown on p. 21, a suspension of LiOCH in THF can be obtained by gradually replacing the ammonia of an ammoniacal solution of the acetylide by THF. The lithium acetylide obtained in this way probably thanks its stability to the complexed ammonia. In the procedure described below, butanal is added to the suspension to give the acetylenic carbinol in a reasonable yield. Since this compound is rather volatile, it is essential to remove the greater part of the THF, before the hydrolysis is carried out. The main solvent which then has to be removed in the isolation procedure is the diethyl ether, used for the extractions. During the addition of the aldehyde, acetylene is introduced to suppress the formation of the diol RCH(OH)C=CCH(OH)R. 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

A vinylogous Mukaiyama reaction, similar to that utilized in our synthesis, was employed to introduce the C-, stereocenter in Nicolaou s synthesis and also in the synthesis of preswinholide A reported by the Nakata group I53k One notable reaction in Nakata s synthesis of preswinholide A was the auxiliary-controlled aldol reaction shown in Scheme 9-31. Here the Evans auxiliary is used to couple two relatively complex fragments 91 and 92 to give 93. Unusually, this reaction was best performed using the lithium enolate of imide 91. 

Other fates are possible for the enolate formed in the initial conjugate addition and an obvious possibility is an aldol reaction. With an asymmetric catalyst, the combination of three simple molecules leads to one enantiomer of one diastereoisomer of the tandem Michael-aldol product14 83. The catalyst 84 is based on a BINOL A1 complex (see chapters 25, 26). It can be drawn either as a lithium salt with an aluminium cation or, better, as a lithium aryloxide with a Lewis-acidic aluminium atom. This is better because both basic ArCT and Lewis acidity are necessary for catalysis. 

An aluminum-lithiiun catalyst, (R)-ALB, prepared from (R)-BINOL, and lithium aluminium hydride promoted the addition of malonate to 23 giving (R)-44 in 99% ee. X-ray analysis of the ALB catalyst showed an aluminum ate complex structure with li coordination to the oxygen atom. The asymmetric tandem Michael-aldol reaction of 46 was conducted with this catalyst giving a single isomer 47 containing three asymmetric centers. The aluminum enolate under-... 

The stereoselectivity of the antibody-catalyzed addition of acetone to aldehyde 67 revealed that the ketone was added to the re-face of 67 regardless of the stereochemistry at C2 of this substrate. The aldol process follows a classical Cram-Felkin mode of attack on (S)-67 to generate the (4S,5S)-68 diastereomer and the anti-Cram-Felkin mode of attack on the (R)-67 to yield the (4S,5R)-69 diastereomer. The products are formed at a similar rate and yield, therefore there is no concomitant kinetic resolution of the racemic aldehyde. The two antibodies differ in their diastereofacial selectivity, reflecting the ability of the antibodies to orient the 67 on opposite sides of the prochiral faces of the nucleophilic antibody-enamine complex of acetone. Heath cock and Flippin [79] have shown that the chemical reaction of the lithium enolate of acetone with (S)-67 yields the (4S,5S)-68 diastereomer a 5% de for this Cram-Felkin product. The generation of the (4S,5R)-69 and (4R,5R)-70 products in a ratio of 11 1 by the... 

Cyclic cobalt-acyl complexes can be deprotonated, and subsequent reaction of these enolates with aldehydes gives predominantly the anti/threo product (Scheme 63). Rhenium-acyl complexes can be deprotonated in the same manner. These lithium enolates can be alkylated or can react with [M(CO)5(OTf)] (M = Re, Mn) to give the corresponding enolates (Scheme Many transition metal enolates of type (21) or (22) are known, - but only a few have shown normal enolate behavior , e.g. aldol reaction, reaction with alkyl halides, etc. Particularly useful examples have been developed by Molander. In a process analogous to the Reformatsky reaction, an a-bromo ester may be reduced with Smia to provide excellent yields of condensation products (Scheme 65) which are generated through intermediacy of a samarium(III) enolate. ... 

On the other hand, it has been found that (3-lactams having other substituents at C-1 and C-4 give complex isomer mixtures.A typical example is shown in equation (95) anti and syn aldols (139) and U40) are formed in excellent yield, but in a ratio of 1 1. Another example is seen in the reaction of 3-lactam (141 R = SPh) aldols (142) to (145) are produced in a ratio of 34 27 11 23 (equation 96). Similar results are obtained with the 4-trityl derivative (141 R = CPha) aldols (142) to (145) are formed in a ratio of 32 39 12 l . However, the lithium enolate of 3-lactam (146) reacts with acetaldehyde to give a single aldol (147) in 80% yield (equation 97) The implication from these results is that the meth-oxymethyl group in (146) effects the stereoselectivity, both facial and simple, by coordination of the lithium cation. Again, (147) has anti aldol stereochemistry, as is expected for an ( -enolate. 

Davies and Liebeskind independently prepared chiral aluminum enolates from enantiomerically homogeneous acyl-iron complexes (137) and recorded the first aluminum-mediated asymmetric aldol reactions. Although the lithium enolate of the chiral iron complex (CHIRAC) provides aldol products with... 

Asymmetric aldol reactions are also possible with chiral propanoyl-iron complexes, as shown in Scheme 62. ° Good to excellent stereoselectivities for anti aldol products (140) are obtained when the lithium enolate of the propanoyl-iron complex is treated with 3 equiv. of EtaAlCl at -40 °C, followed by an aldehyde at -100 °C. Interestingly the same reaction using CuCN instead of Et2AlCl provides exclusively syn aldol products (141). 

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