Disconnections starting materials

Disconnection An analytical operation, which breaks a bond and converts a molecule into a possible starting material. The reverse of a chemical reaction. Symbol and a curved line drawn through the bond being broken. Called a dislocation by some people. 

This is a good opportunity to mention our third criterion for a good disconnection - that it leads to recognisable starting materials. We have used this criterion already in frames 20 and 42. 

Choosing this disconnection because we recognise a starting material easily made by a Diels-Alder reaction (cf. frame 22). 

Synthesis Though we could follow the stepwise pattern of the disconnections, it is easier to add an activating group to the acetone molecule so that our starting materials are two molecules of acetoaeetate and formaldehyde. It turns out that Hagemann s ester can be made in two steps without having to alkylate the Mannich base ... 

Now disconnect any bond joining two common atoms and see if there is a good starting material. 

So we realljr need to disconnect 351A and B and 352A. Analj se possible disconnections of these three on the same chart since they will have several starting materials in common. 

Analysis continued I suggest to give 383A since one can then disconnect the a,p-unsaturated ketone and get a starting material with only one ring ... 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

We close the section on open-chain molecules with an example of a trifunctional target molecule. This does not include any fundamentally new problem. In antithetic analysis one simply chooses an appropriate difunctional starting material, which may be further disconnected into monofunctional starting materials. 

The retrosynthetic analysis presented in Scheme 6 (for 1, 2, and 16-19) focuses on these symmetry elements, and leads to the design of a strategy that utilizes the readily available enantiomers of xylose and tartaric acid as starting materials and/or chiral auxiliaries to secure optically active materials.14 Thus by following the indicated disconnections in Scheme 6, the initially generated key intermediates 16-19 can be traced to epoxide 23 (16,19 =>23),... 

Look for substituents which are difficult to add. It is often good strategy not to disconnect these at all, but to use a starting material containing the substituents. 

Disconnection at any of these positions is possible (12a). We might prefer a central disconnection (b or c) first (see Chapter T 11) but we shall end up with Me NH, two molecules of ethylene oxide, and the phenol (13) as starting materials. 

Ansiser There are 1,2-diX and 1,3-diX disconnections to bo made, giving (17) as the starting material which could be made by the bromination of enone (18). 

AnBwep Disconnection back to the first branchpoint ( in 14a) requires formaldehyde and halide (15) which comes from alcohol (16). Disconnect ion back to the second branchpoint ( in 16) gives two available starting materials. 

Answer We obviously want to discontioct on the more substituted side and (a), (b) and (c) are all possibi Disconnection (c) has the advantage that it is betweer two branchpoints and so gives two simple starting materials. 

The obvious Vfittig disconnection gives stabilised ylid (5fi) and keto-aldehyde (57). We have used many such long-chain dicarbonyl compounds in this Chapter and they are mostly produced from available alkenes by oxidative cleavage (e.g. ozonolysis). In this case, cyclic alkene (58) is the right starting material, and this can be made from alcohol (59) by elimination,... 

Answer Acetylene (24) will give both by reduction under the right conditions (p T127), Further disconnections give simple electrophilic starting materials. 

Simple Problem Find the Dicls-Alder disconnections in the following molecules and draw the starting materials. 

Both disconnections on symmetrical (4) should be carried out as very simple starting materials result. ... 

Simpls Probl m3 Make disconnections on these TMs and write the starting materials. 

Write disconnections and starting materials forthi.> i-hydroxy carbonyl compounds. 

The most important of these three types of target innlecule is the a, S-unsaturated carbonyl compound. Disconnect TMs (10) and (11) and provide starting materials. 

As a model for his synthesis of vitamin D, Lythgoe " made triene C 2). Disconnection (Wittig) of the central double bond is likely to give the greatest simplification and an a-methylene ketone (43) is one of the starting materials. 

Problem Carry out both the reverse Michael disconnections on TM(1), continue the analysis to find available starting materials, and choose which route you pre.Cer. 

The analysis uses the same starting material s whichever bond you disconnect iirst raalonate ester, PhCHO, and the specific enolate (2). This last could be an enamine, or an activated version (4) (cl p T 160 ff ) ... 

Answer The cyclohexenone is a clue to a Robinson annelation disconnection reveals symmetrical amino ketone (26) as starting material (see page T 147 ior its synthesis). An enamine is again the best control. Ana lysis... 

Now the ether may be disconnected, diol (13) being the obvious starting material. This contains an i-hydroxy ketone so we might consider disconnecting an acyl anion equivalent from a ketone. If we use an acetylene, the starting material (14) is symmetrical so hydration presents no problems,... 

Enone disconnect Ion gives hydroxyketone (42) used as a starting material on p T 195. 

Opening the anhydride and writing the enol as a ketone reveals that we are trying to make an a-ketoacld (51), The best disconnection Is (51a) which uses the 1.3-dlcarbonyl relationship, Is next to a branchpoint, and produces a symmetrical starting material (52), Ana lysis... 

Disconnecting the lactone gives hydroxyacid (48), With succinic anhydride In mind as an available 1,4-dl-carbonyl starting material, we can write keto acid (49) as an intermediate and the orientation is then correct for a Frledel-Crafts disconnection as both MeO and He activate this position. 

Dicarbonyl disconnection of symmetrical (38) again reveals a suitable 1,6-dicarbonyl starting material (39) but reconnection gives an impossibly strained alkene (40). 

---