D2 synthon

Dioxo compounds are deprotonated at C-2 and C-4 by two equivalents of strong bases (e.g. LDA or BuLi). Carbon atom C-4 of those dianions is much more nucieophilic than the less basic center C-2 (Hauser s rule C.R. Hauser, 1958 K.G. Hampton, 1965). The formation of some typical d2-synthons and their pA values are given below. 

Aldol additions and ester condensations have always been and still are the most popular reactions for the formation of carbon-carbon bonds (A.T. Nielsen, 1968). The carbonyl group acts as an a -synthon, the enol or enolate as a d2-synthon. Both reactions will be treated together here, and arguments, which are given for aldol additions, are also valid for ester condensations. Many famous name reactions belong to this category ). The products of aldol additions may be either /9-hydroxy carbonyl compounds or, after dehydration, unsaturated carbonyl compounds. 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of o-bromo carbonyl compounds (a2-synthons) with enolate type anions (d2-synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

The synthons 9 and 15 have natural polarity and it will be helpful in the next 10 chapters if you recognise whether synthons such as these and 17 have natural polarity. We have discussed 9 and 15 above and 17 in chapters 6 and 13 where we used a,p-unsaturated compounds 18 as electrophiles. You may find it helpful to use the labels suggested by Seebach.1 The letters a and d are used for acceptor (electrophilic) and donor (nucleophilic) synthons and a superscript number shows which atom is meant. The carbonyl group is always atom number 1. So the enolate becomes a d2 synthon and 9 and 17 are a1 and a3 synthons. If you don t like these labels, ignore them, they are entirely optional. 

So if we wish to make a compound like 19 we can disconnect a C-C bond to reveal two synthons, 20, a d2 synthon easily recognised as the enolate of ketone 22, and an a1 synthon 21 realised in the aldehyde 23. We have rediscovered the aldol reaction. 

Another odd-numbered relationship means we can still use synthons of natural polarity. The 1,5-diketone 1 disconnects to a d2 synthon, an enolate, and an a3 synthon 2, that you should realise (chapter 6) is represented by the reagent 3. The conjugation in the enone makes the terminal carbon atom electrophilic. 

We can classify the synthons further according to where the functional group is in relation to the reactive site, The first synthon in the diagram below, whieh corresponds to an aldehyde, we call an a synthon, because it is an acceptor that carries a functional group on the same carbon as its reactive eentre, The second is a d2 synthon because it is a donor whose reacting site is in the 2-position relative to the carbonyl group, Earlier you met two other types of synthon, corresponding to epoxide and Michael acceptor, and we can now classify these as a2 and a3 synthons,... 

We csll this disconnection a two-group C-C disconnection, because we are using the OH and the C=0 groups together to guide our disconnection, The disconnection gives us a d2 synthon for which we shall use an enolate equivalent, and an a1 synthon, for which we shall use an aldehyde or a ketone,... 

A good equivalent for the ester enolate d2 synthon is a p-dicarbonyl compound, because it can easily be disconnected to diethyl malonate and an alkylating agent. 

You will perhaps realise from these particular examples that the d2 synthon will be represented in real life by an enolate or its equivalent and the a3 synthon by an a, 3-unsaturated carbonyl compound, both displaying the natural polarity of these fragments. It is generally true that even numbered donor synthons (d2, d4, etc.) and odd numbered acceptor synthons (a1, a3, etc.) have natural polarity while the odd numbered donor synthons (d1, d3, etc.) and the even numbered acceptor synthons (a2, a4, etc.) have unnatural polarity or umpolung. This makes the numbering of such synthons a useful quick check on the type of reagent likely to be needed. 

C2-homologizati on of sugars with, 264-265 Acetamide, JV-bromo- (AcNHBr, NBA) bromohydrination with, 275-276, 287 Acetaminophen (= paracetamol), 301 Acetate, piperidinium cat. for aldol add., 82 —, sodium a-epimerization of ketones, 277 opening of oxiranes, 282 Acetic acid, anhydride (AcfO) protection with. See Protection Pummerer rearr. with, 51, 265 —, esters (See also Protection of hydroxy groups) C-H acidity, 10 1-methylethenyi ester pr., 174 transenolization, 58 —, bromo-, esters pr., 179 a2-synthon, 19, 65, 309 d2-synthon, 19, 301 —, chloro-, esters pr., 179 hydantoins from, 308 —, cyano-, esters pr., 177 pyrrolines from, 298 —, (dialkoxyphosphinyl)-, esters pr 188 Wittig-Horner olefinations, 267, 282 —, diazo-, ethyl ester pr, 176, 178 cyclopropanes from, 74—75 —, dichloro- deblocking of pixyl ethers, 342 —, hydroxy-, esters pr., 176 —, hydroxyphenyl-, (S)- (l-mandelic acid) ... 

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