Unnatural synthons

This is a l,4 diketone and disconnection of the central bond separates the two rings. We require a specific enol equivalent lor (4) - they used activated ketone (6) - and a reagent for unnatural synthon (5) -they used a-chloroketone (7). 

A simple example is the cyclopentenone 7 because the keto-aldehyde 8 can cyclise only one way as the aldehyde cannot enolise. The best 1,4-dicarbonyl disconnection is probably 8 giving some enolate equivalent 10 of isobutyraldehyde and a reagent for the unnatural synthon 9 such as the bromoketone 11. 

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. 

The problem of an unnatural (illogical) synthon arises here too (cf. Chapter 23). A 1,4-diketone (1) can be disconnected at its central bond into the natural enolate (2) but that requires also an unnatural synthon, the a-carbonyl cation (3). We shall need reagents for this synthon as well as for related synthons at different oxidation levels. We met some of these reagents—a-halo carbonyl compounds and epoxides—in Chapter 6. 

At the alcohol oxidation level (12), epoxides (14) are the obvious reagents for the unnatural synthon (13). The trans hydroxy acid (15) was needed for ... 

Allyl (7) and propargyl (22) haiides can act as latent unnatural synthons (24) and (2S) respectively by electrophilic addition to the double bond in (21) or hydration of the triple bond in (23). If the nucleophile is an enolate ion, a... 

Unsaturated ester (8) is made by dehydration of alcohol (9). The next disconnection should be of bond (a) in (9) but this needs the unnatural synthon... 

Unsaturated ester (8) is made by dehydration of alcohol <9). The next disconnection should be of bond (a) in (9) but this needs the unnatural synthon <10). A better strategy is to change the 1,4-relationship in (9) into a 1,3-relationship (11) by removing the CHa group so that natural synthon (12) can be used. 

Simple reactivity inversion" implies using an umpoled synthon whose origin has, in principle, nothing in common with the synthon with "unnatural" polarity. An example of this type of reactivity inversion is found in one of the possible synthesis of cw-jasmone (3) in which the nitroethane (4) is used as an equivalent of an "acetyl anion" and reacts with an a,P-unsaturated ketone to give the corresponding 1,4-bifunctional system which can then be transformed by a Nef-type reaction into the dissonant 1,4-dicarbonyl system [5]. An intramolecular aldol condensation finally affords the target molecule (Scheme 5.3). 

TABLE 5.2. Umpoled synthons and their equivalent fragments with unnatural... 

To a first approximation, the chiral discrimination should be independent of the nucleophile. The palladium-catalyzed desymmetrization protocol utilizing a heterocyclic nucleophile provides enantio- and diastereoselective entries to diverse carbo-nucleosides. As shown in Scheme 8E.9, introduction of purine bases rather than the hydroxymethyl synthon also affords high enantioselectivities [61]. A variety of natural and unnatural nucleosides can be flexibly prepared because the simple change of ligand chirality or, alternatively, switching the alkylation sequence leads to opposite enantiomers. The palladium-catalyzed approach sharply contrasts with the chiral-pool method, whose enantiodivergency is limited by the availability of the starting material. 

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. 

For this reason, our chapters on two group C-C disconnections follow a slightly odd order. First we deal with the odd numbered relationships the 1,3-diCO 19a (chapter 19) and the 1,5-diCO 24a (chapter 21) and then we turn to the even-numbered relationships 1,2-diCO 27 (chapter 23) and 1,4-diCO 28 (chapter 25) because these will need synthons of unnatural polarity. Finally we shall turn to the 1,6-diCO relationship (chapter 27) as that involves a totally different strategy. 

Synthesis of difunctionalised compounds with even numbered relationships needs some synthons of unnatural polarity. 

All odd numbered acceptor synthons (such as a1 and a3) and even numbered donor synthons (such as d2 and d4) have unnatural polarity. 

The nitro group is remarkably versatile and solves otherwise difficult problems. The table is meant to help you see which synthons can be represented by nitro-compounds. Note particularly that the charged synthons all have unnatural polarity and the primary enamine in the Diels-Alder entry could not be made without protection of the amine. 

In chapters 19 (1,3-diCO) and 21 (1,5-diCO) we were able to use an enol(ate) as the carbon nucleophile when we made our disconnection of a bond between the two carbonyl groups. Now we have moved to the even-numbered relationship 1,2-diCO this is not possible. In the simple cases of a 1,2-diketone 1 or an a-hydroxy-ketone 4, there is only one C-C bond between the functionalised carbons so, while we can use an acid derivative 3 or an aldehyde 5 for one half of the molecule, we are forced to use a synthon of unnatural polarity, the acyl anion 2 for the other half. We shall start this chapter with a look at acyl anion equivalents (d1 reagents) and progress to alternative strategies that avoid rather than solve the problem. 

The problem of unnatural polarity also arises in making C-C disconnections for the synthesis of 1,4-difunctionalised compounds. If we start with 1,4-diketones 1, disconnection in the middle of the molecule gives a synthon with natural polarity 2, represented in real life by an enolate 4, and one of unnatural polarity, the a2 synthon 3 represented by some reagent of the kind we met in chapter 6 such as an a-haloketone 5. 

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. 

Synthesis of Natural and Unnatural Products from Sugar Synthons... 

D-Proline (16) is an unnatural amino acid and an important chiral synthon for the synthesis of a variety of biologically active compounds. There are few chemical methods for asymmetric synthesis of this compound. Almost all processes for the production of D-proline at scale are based on resolution of d/-prolinc, and most of them involve the racemization of L-proline (17). 

Not unnaturally, the synthesis of a pyrazine or hydropyrazine from a single C—N—C—C—N—C synthon is rare. However, the cyclization of A,A -dibenzyli-dene or NJV -diacyl derivatives of ethylenediamines has proven possible, as indicated in the following examples ... 

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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