Umpolung equivalents

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. 

B.ii. Acyl Anion Equivalents. The most common umpolung equivalent is that for acyl anion 339, and dithianes 344 are the most common reagent used for this purpose. Dithiane 344 is prepared from an aldehyde, but ketones are also precursors (sec. 7.3.B.ii). Removal of the hydrogen adjacent to the sulfur requires a base such as n-butyllithium and the product is a-lithiodithiane (345). The acidity of this hydrogen is largely... 

B.V. A R(C=0)CH2CH2CH2+ Equivalent. In this umpolung equivalent, the potentially positive center is even further removed from the carbonyl (see 342 in Table 8.18). This umpolung equivalent is best achieved by reaction of a nucleophile with a vinylogous ketene dithioacetal such as 395.376 initial reaction of... 

B.vi. An R(C=0)CH2CH2CH2CH2" Equivalent. The final umpolung equivalent in Table 8.18 is 343, where the reactive center is separated from the carbonyl by three carbons. This umpolung equivalent is... 

Another group of synthetic equivalents has been developed which correspond to the propanal homoenolate, CH2CH2CH=0. This structure is the umpolung equivalent of an important electrophilic reagent, the a,jS-unsaturated aldehyde... 

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. 

Sulfur compounds are useful as nucleophilic acyl equivalents. The most common reagents of this type are 1,3-dithianes, which on lithiation provide a nucleophilic acyl equivalent. In dithianes an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. The lithio derivative is a reactive nucleophile toward alkyl halides and carbonyl compounds. 11... 

Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an example of umpolung. 

The benzoin reaction dates back to 1832 when Wohler and Liebig reported that cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal example in which the normal mode of polarity of a functional group was reversed (Eq. 1) [26], This reversal of polarity, subsequently termed Umpolung [27], effectively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent. 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

The realization of the principle of umpolung , in which reactivity at a normally electrophilic site is inverted to that of a nucleophilic species,161 has resulted in the development of numerous masked acyl anion equivalents for carbon-carbon bond formation.162 The use of masked acyl anion equivalents for conjugate additions was made possible by several observations. First, Stork reported that protected cyanohydrins afforded preferential kinetic 1,4-addition with ot, 3-enonesl6b and second, Brown reported that preferential kinetic 1,4-addition of 1,3-dithianes was effected by the use of HMPA.163... 

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. 

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. 

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. 

In both reactions cyanide has usually been employed as catalyst [231, 232], Under these conditions, the acyl anion equivalent is represented by the tautomeric form XIX of the cyanohydrin anion which results from addition of cyanide to an aldehyde (Scheme 6.104). In nature, this type of Umpolung is performed enzymatically, with the aid of the cofactor thiamine pyrophosphate 226 (vitamin Bl, Scheme 6.105) [232, 233]. 

Umpolung. Show how each of the following compounds can be prepared from the given starting material using either a formyl or an acyl anion equivalent in the synthetic scheme. 

We present here a reversible umpolung of a,p-ethylenic ketones and aldehydes, in which the ylides3are synthetic equivalents of P-acylvinylanions in two unlike pathways (i) and (ii) (Scheme T, see next page). 

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