Homoenolate synthons

A completely different approach to lithium homoenolate synthons uses a carbon-oxygen bond cleavage. Lithiation of acrolein diethyl acetal 180 with lithium and a catalytic amount of DTBB (2.5%) in the presence of different carbonyl compounds in THF at 0°C gave, after final hydrolysis, the corresponding y-products 181 in different diastereomeric ratios (Z/ 3/1 to 20/1) (Scheme 63) . 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

The aldehyde homoenolate synthons discussed above do not add to aldehydes with a high degree of stereoselectivity. However, transmetalation to aluminum or titanium... 

The unsaturated version of the homoenolate synthon, the 3-acyl vinyl anion80 133, can be generated simply in the carboxylic acid series from the halide 134, and has been used in butenolide 135 synthesis81. ... 

Addition of trivalent phosphorus siloxanes with a, -unsaturated aldehydes gives high yields of (34), which can be easily deprotonated to give (35 Scheme 17). Here again, electrophiles react at the 7-position either exclusively or predominantly. The dianion (33 R = Ph equation 12) reacts with excess methyl iodide and subsequent methanolysis affords a mixture of (36) and (37). Thus, (36) most closely approximates the binucleophilic homoenolate synthon (4 Scheme l). ... 

Allyl anions (38a),(38b) and (38c) exhibit a similar regioselectivity toward electrophiles, and thus serve as homoenolate synthons. Addition of titanium tetraisopropoxide to (39) followed by condensation with aldehydes gives the anti adducts exclusively, which can be converted to the (Z)-1,3-dienes upon treatment with methyl iodide (Scheme 18). The ( -1,3-dienes can be prepared from the lithiated allyldiphenylphosphine oxide. The stabilized allylic phosphonate anion (40) condenses with carbonyl... 

Homo-DNA, 344-345 Homoenolate synthons, 14-15, 70, 76 L-Homoproline FK 506 synthon, 324, 326—327 Homer olefinatlon 28-30... 

I.3.3.2.3.2. Reagents Representing y-Hetero-, a,y- and y,y-Bis(hetero)-Substituted Allyl Anion Synthons, Including Homoenolate Reagents... 

Allyl anion synthons A and C, bearing one or two electronegative hetero-substituents in the y-position are widely used for the combination of the homoenolate (or / -enolate) moiety B or D with carbonyl compounds by means of allylmetal reagents 1 or 4, since hydrolysis of the addition products 2 or 5 leads to 4-hydroxy-substituted aldehydes or ketones 3, or carboxylic acids, respectively. At present, 1-hetero-substituted allylmetal reagents of type 1, rather than 4, offer the widest opportunity for the variation of the substitution pattern and for the control of the different levels of stereoselectivity. The resulting aldehydes of type 3 (R1 = H) are easily oxidized to form carboxylic acids 6 (or their derivatives). 

A CH-group, which bears vinyl and sulfide substituents, is acidic enough to be metallated by strong bases. Other d3-synthons may contain two activating functional groups in Imposition ( homoenolate -equivalents). Only one of the a-carbons is deprotonated under appropiate conditions (e.g. succinic diesters). Ano ther possibility is an acidic carbon and a non-acidic functional group in 1,3-positions (e.g. propargyl derivatives). Silyl ethers of a, -unsaturated alcohols can also be converted to anions, which react as d3-synthons (W. Oppolzer, 1976). 

Another common umpolung synthon is a homoenolate. Normally the ft position of a carbonyl compound is an electrophilic center (by Michael addition to an 0, /3-unsaturated carbonyl derivative). To make it a nucleophilic center, an organometallic is needed since it is unactivated and nonconjugated. A common way to do this is to use a /3-bromo acetal. 

You might think you could escape this problem by choosing the alternative disconnection 8, but this is not so. We have more choice here we can use the a3 synthon 7 with natural polarity, in real life an enone, but then we shall have to use the acyl anion equivalents 6 that we met in chapter 23. Reversing the polarity gives us the naturally polarised electrophile, an a1 synthon 9 represented by an acylating agent and the homoenolate, or d3 synthon, 10 with unnatural polarity. 

The same disconnection but of the opposite polarity requires some acylating agent for synthon 9 this is no problem as we have various acid derivatives at our disposal. But the nucleophilic synthon 10, a d3 synthon or homoenolate, is another matter. There is no stabilisation of the anion as drawn but if it were to cyclise to the oxyanion 56, it would be rather more stable and there is evidence-trapping with silicon to give 57 for example-that this can occur. 

We can continue both strategies by disconnections at the branchpoint, each needing simple aryl ketones 16 and 18, but 15b requires a homoenolate reagent for the d3 synthon 19 and we should rather avoid that, while 15c needs a simple enolate 17 and we prefer that. 

The cyclic acetal is a protected form of the hydroxy-aldehyde and oxidation under acidic conditions (Cr03 in H2S04) gives a good yield of the spirocyclic lactone. In the whole process from allyl silane to lactone, the allyl silane is behaving as a d3 synthon or homoenolate. 

The title transformation provides an alternative pathway for the construction of the cyclopropane ring from a synthon of three carbons. The intramolecular cyclization of homoenolate anion equivalents is represented in Scheme 11, Eq. (ii). In practice, several routes involving metals such as Mg, Zn, and Ti, as well as different homoenolate precursors, have been developed [17a-e]. 

Metalated SMP allylamines or enamines have been used as the first chiral homoenolate equivalents (d synthons eq 5). ... 

Enolisation 1 involves the removal of the a-proton from a carbonyl compound to form an enolate ion 2. Homoenolisation involves the removal of a (i-proton 3 to form the homoenolate ion 4 or 5. Both the enolate and the homoenolate can be represented as carbanions, but whereas the enolate version 2b is merely a different way of representing a single delocalised structure, the homoenolate 5 is a different compound from the cyclopropane 4. No literal examples of homoenolates 5 are known so they have the status of synthons which may be represented in real life by reagents derived from cyclopropanols 4 among many other possibilities.1... 

The acyl cation 2a or acylium ion 2b is a familiar intermediate in the Friedel-Crafts reaction. It is easy to make (acid chloride + Lewis acid 1) and it can be observed by NMR as it expresses the natural reactivity pattern of the acyl group. The acyl anion by contrast has umpolung or reverse polarity.1 One might imagine making it from an aldehyde by deprotonation 3 and that it would be trigonal 4a or possibly an oxy-carbene 4b. Such species are (probably) unknown and their rarity as well as their potential in synthesis has led to many synthetic equivalents for this elusive synthon. The acyl anion, the d1 synthon, is the parent of all synthons with umpolung2 and should perhaps have been treated before the homoenolates dealt with in the previous chapter. 

The synthetic value of homoenolates, in exact analogy to that of enolates, stems from their amphoteric nature (equations 1 and 2). In addition, homoenolates represent archetypal synthons in the concept of umpolung , acting as inverse polarity nucleophilic synthons of Michael acceptors. 

The nucleophilicity of the Breslow intermediate can be transferred to the p-position of an ot,p-unsaturated aldehyde when this reacts with a NHC, generating a homoenolate that can act as a d -synthon (Scheme 2.22). 

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