Umpolung Synthons

Because of die polarities associated witii carbonyl groups, some difunctional compounds are much easier to produce than others. For example, 1,3-dicarbonyl compounds and 1,5-dicarbonyl compounds are easy to produce using standard retrosynthetic steps with normal polarities induced by the carbonyl group. 

In contrast, 1,2-dicarbonyl compounds or 1,4-dicarbonyl compounds are more difficult to disconnect by valid retrosynthetic steps. Consider a 1,2-diketone. Disconnection of die bond between die carbonyl groups requires that one of the carbonyl groups has the normal electrophilic character, but die other carbonyl carbon must have nucleophilic character (an acyl anion or its equivalent), which is not die normal polarity of a carbonyl group. 

In the same way, disconnection of a 1,4-diketone requires either an acyl anion equivalent reacting with a normal /3-carbonyl electrophile or a normal o -carbonyl nucleophile reacting with an abnormal cr-carbonyl electrophile. These abnormal or reversed-polarity reagents are said to have umpolung reactivity. 

Likewise 1,3-dithianes can be deprotonated by alkyl lithium bases and the resulting anions are strong nucleophiles. The ditliiane group can be hydrolyzed back to the carbonyl group. Thus the dithiane serves as a synthon for the acyl anion. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

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These are only three of many ways that have been reported for the formation of acyl anion equivalents, which are among the most common umpolung synthons to be found in the literature. All are prepared by a similar strategy in that they contain functional groups which can sustain a negative charge on an adjacent carbon and can be converted back to a carbonyl group. 

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. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Fermenting baker s yeast also catalyzes the 1,4-addition of a formal trifluoroethanol-d1-synthon to a,/i-unsaturated aldehydes, to give optically active l,l,l-trifluoro-2-hydroxy-5-alka-nones52. Presumably, the mechanism involves oxidation of the alcohol to the corresponding aldehyde followed by an umpolung step with thiamine pyrophosphate and Michael addition to the a,/i-unsaturated aldehyde. For example, l,l,l-trifluoro-2-hydroxy-5-hexanone (yield 26%, ee 93%) is thus obtained from trifluoroethanol and l-bnten-3-one. 

The substitutions at C-l can be classified as processes with umpolung of reactivity since a negatively charged carbon directly connected to oxygen is involved. A variety of synthons with umpolung of reactivity are therefore derived from simple alkoxyallenes as summarized in Scheme 8.4. The rich and often very surprising chemistry of these unique, but easily available, building blocks is still under development and it is expected that even more new synthons derived from alkoxyallenes will be detected in the future. 

Although all these strategies imply, in some respect, a reactivity inversion of some of the starting reagents or synthons, the term "reactivity inversion" (or Umpolung as proposed by Seebach in 1979) [1] is commonly used in the context of the strategy known as "illogical disconnections" [2]. 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

Re, R-0=0, CH2-C02R. These synthons have unnatural , or reversed polarity (originally called umpolung ).23 However, they are perfectly valid though their reagent equivalents are sometimes not immediately obvious. Some illustrative examples are noted below. 

You have in fact met one example of each of the unnatural synthons with a2 and d1 reactivity. Such synthons are given the German name Umpolung, meaning inverse polarity because their natural reactivity is reversed, and umpolung reagents are the key to the synthesis of 1,2- and 1,4-difunc-tionalized compounds. 

We shall finish this chapter by looking at disconnections of 1,2- and 1,4-difunctionalized compounds because these require us to use reagents with umpolung equivalent to d1, d3, a2, and a4 synthons. There are very many reagents for these synthons—if you are interested to learn more, consult a specialized book. 

If we attempt the disconnection of one of the other bonds, two possibilities are available because the two fragments are different. We can use either ad1 -fa3 strategy or an a1 + d3 strategy. In each case w have one natural synthon and one with umpolung. 

Interestingly, deprotection (hydrolysis) of the heterocyclic auxiliary exposes a synthetically useful carbonyl group. This is possible in our system since the auxiliary is bonded to the carbonyl group by a carbon atom rather than a heteroatom. Such hydrolyses are well established for 1,3-dithiane derivatives as a result of their ubiquity as synthons for umpolung reactivity of the carbonyl group (Fig. I).5... 

In the Seebach terminology cyclopropanes correspond to synthons having acceptor properties a and donor properties d respectively in a 1,3 distance, whereas the normal 1,2 relationship is valid for olefins. Many synthetic methods with umpolung use this... 

And we know what the reagent was (A). This is a d synthon. Aldehydes are naturally electrophilic at C3 (by conjugate addition) so to make a reagent with unnatural polarity umpolung , p. 798), the aldehyde must be protected. 

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