D1 synthon

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 carbanions derived from thioacetals, however, are typical d1 -synthons. Most frequently used are 1,3-dithianes and C-silylated thioethers (see p. 33f. D. Seebach, 1969,1973 B.-T. Grobel, 1974,1977). In these derivatives the proton is removed by butyllithium in THF. 

We have met the acyl anion or d1 synthon in chapter 23 but for the disconnection 8 on 1,4-diketones we need a d1 reagent that will do conjugate additions on enones such as 36. Sadly that eliminates dithians from consideration as they are too basic (hard) and tend to add direct to carbonyl groups. 

A better strategy emerges from disconnection of the six-membered ring 44a. Aldol disconnection reveals a triketone with two 1,4-dicarbonyl relationships 49. An ideal disconnection would correspond to a reagent for the d1 synthon 51 that can do conjugate additions to both 50 and 52. 

Amino nitriles are useful for conjugate addition Acyl anion equivalents of the ester d1 synthon - C02R Methods Based on Vinyl (Enol) Ethers and Enamines Lithium derivatives of cyclic vinyl ethers The synthesis of pederin and related anti-tumour agents Lithium derivatives ofallenyl ethers Oxidative Cleavage of Allenes... 

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 yields in these reactions are not wonderful and most syntheses planned with acyl anion or d1 synthons are realised with one of the reagents we are about to describe rather than with acyl-lithiums. Things may change as understanding of these rather reactive intermediates develops. There are three main types of acyl anion equivalent reagents which can be considered as modified acetals, that is protected aldehydes, masked carbonyl compounds such a nitroalkanes, and substituted vinyl-lithiums. The rest of this chapter will be devoted to these reagents. 

The a-hydroxyketone 39 could be made from attack of a d1 reagent on the rather enolisable ketone PhCOMe 42. The reagent chosen for the d1 synthon 43 was again a dithian 44. 

Acyl anion equivalents of the ester d1 synthon C02R... 

The group of antitumour agents related to pederin have a common structural feature 96 of a functionalised tetrahydropyran attached through an amide linkage to a variety of complex amines. In his successful syntheses of these compounds, Kocienski21 chose to disconnect next to the ring and use a reagent 99 for the d1 synthon 97 that would be acylated by the oxalyl derivative 98. 

When Raphael wanted the key intermediate 162 for his synthesis of strigol 160, the aldol disconnection 162a revealed the need for the diketone 163 and hence by disconnection of a very strategic bond, the d1 synthon 164. 

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