Natures acyl anion equivalent

Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions... 

Stork first demonstrated the utility of protected cyanohydrins as acyl anion equivalents in 1971 [2]. The acetal-protected cyanohydrin 8 was transformed into the corresponding anion with LDA in THF/HMPA, which was then alkylated with a range of alkyl halides, including secondary bromides (Scheme 2). A mild acidic hydrolysis yielded a cyanohydrin, which provided the ketone after treatment with base. The Stork cyanohydrin alkylation and its variants have become important methods in natural product synthesis [3,4]. 

The first natural product synthesis that utilized the Stetter reaction was reported by Stetter and Kuhhnann in 1975 as an approach to aT-jasmone and dihydrojas-mone (Scheme 21) [93]. Thiazolium pre-catalyst 74 was effective in catalyti-cally generating the acyl anion equivalent with aldehydes 144 and 145, then adding to 3-buten-2-one 146 in good yield. Cyclization followed by dehydration gives cii-jasmone and dihydrojasmone in 62 and 69% yield, respectively, over two steps. Similarly, Galopin coupled 3-buten-2-one and isovaleraldehyde in the synthesis of ( )-rran5-sabinene hydrate [94]. 

Thiamine-catalyzed transformations are reversible, thus TV,/V-dialkyl hydrazones were selected as alternative acyl anion equivalents that were reported to react with electrophiles without acidic activation.41 One especially reactive example, formaldehyde hydrazone resin 13, was constructed from polymer-supported hydrazines and was employed in the first polymer-supported, uncatalyzed acyl anion additions (Fig. 8).38 As test substrates, nitroalkenes (as Michael acceptors) and activated aldehydes were selected. Reactivity of these acyl anion equivalents depended critically not only on the nature of the starting hydrazine, but also on the protocol for hydrazine formation. 

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]. 

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. 

To gain access to a broader spectrum of natural products including protease inhibitors, C-C-bond formation is often required in central steps. For this purpose polymer-supported carbanion equivalents have been investigated (Chapter 4). Several strategies leading to supported acyl anion equivalents are presented these have been employed for general synthesis of protease inhibitors containing the a-hydroxy-jS-amino motif. 

In Nature the ubiquitous a-hydroxy carbonyl motif is provided by acyl anion equivalents derived from thiamine pyrophosphate (vitamin Bi) as enzymatic cofactor. Thus our synthesis of compounds 8 was based on the construction and in-... 

Nature s acyl anion equivalent (d1 reagent) is thiamine pyrophosphate... 

Hie anions of 68 and 79 are then useful acyl anion equivalents, but in natural product syntheses they are far less popular than reagents containing two sulphur atoms54, particularly dithians55. The chemistry of dithians, e. g. 86 and 87 has been well explored and they have been used in the synthesis of many natural products . The synthesis56 of the Douglas-Fir tussock moth sex pheromone 88 is an example of the way a dithian 86 acts as an acyl anion equivalent in ketone syntheses. 

The 1,3-polyol system is prevalent in a variety of marine natural products. This interesting arrangement of hydroxyl groups can be assembled using aldehydes 574, 575, and 1,3-dithiane as an acyl anion equivalent (Scheme 83) [138]. 

There was essentially one main approach (with a number of buUt in fallback strategies) that was convergent in nature and relied heavily on an acyl anion equivalent (10) to introduce both halves (LHF 11 and RHF 12) and also acted as the spiroketal carbon center in the ketone oxidation state (i.e., 13). Ketone 13 could then be treated with acid to cyclize the linear precursor to EBC-23 (1), driven thermodynamically by the anomeric effect (Scheme 1). 

Meyers, A. I. Heterocycles in Organic Synthesis Wiley-Interscience, 1974 (332 pages). DegITnnocenti, A. Pollicino, S. Capperucci, A. Synthesis and Stereoselective Functionalization of Silylated Heterocycles as a New Class of Formyl Anion Equivalents Chemical Communications 2006, 4881—4893. Yus, M. Najera, C. Foubelo, F. The Role of 1,3-Dithianes in Natural Product Synthesis Tetrahedron 2003, 59, 6147-6212. Albright, J. D. Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins and a-Dialkylaminonitriles Tetrahedron 1983, 39, 3207-3233. Seebach, D. Corey, E. J. Generation and Synthetic Applications of 2-Lithio-l,3-dithianes /. Orpi. Chem. 1975, 40, 231-237. 

Another natural carbon-carbon bond-forming process that has been adapted for use by synthetic chemists involves thiamine, or vitamin Bi, shown on p. 1058. Thiamine plays an essential role in several biochemical processes, including the biosynthesis of sugars, as we shall see in Chapter 24. Real Life 23-2 describes how thiamine also mediates sugar metabolism by converting pyruvic acid, a product of sugar metabolism, into acetyl CoA (Section 19-13). The relevant carbon-carbon bond-forming process makes use of a new kind of nucleophile derived from aldehydes and ketones, an acyl anion equivalent. 

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. 

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