Ketones disconnections

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). 

Ij ample Compound (21) is a P-hydroxy ketone. Disconnect ion of the usual bond reveals two molecules of onone (22), disconnected in turn to two molecules of acetone,... 

In the case of cyclopropyl methyl ketone, disconnection of either the 1,2- or 1,3-carbon-carbon bond of the cyclopropane ring results in the preferred charge distribution shown in (4), namely, the carbanion site is adjacent to the meso-merically stabilising carbonyl group, and the carbocation site may be viewed as a halide-carrying carbon. The reagent equivalent may therefore be 5-chloro-pentan-2-one. 

The second compound is not a lactone as it might first appear, but a ketone. Disconnectic-a C-0 bond reveals an a,P-unsaturated ketone made by an aldol reaction from a hydroxy - with a 1 2-diO relationship. Again, an acyl anion equivalent looks best. The published syrtt r offers the two alternatives shown. Reaction of the hydroxy-ketone with PhCHO and base shown), followed by acid-catalysed cyclization, gives the target molecule. 

Geranyl acetone (57), a natural product also manufactured at BASF, can be made the same way as it too is a 7,5-unsaturated ketone. Disconnection with allylic inversion gives (58) which can be made from (52). 

This is then a general synthesis for ketones and the corresponding disconnection is... 

Now we can disconnect the ketone using our synthetic equivalent for the acetone anion ... 

The section on control showed how we could make ketones by one discoimection. You already know another. How could you make this ketone (TM 61) by the disconnection shown ... 

There is one special case worth discussing in some detail. When yinyl ketones (e.g. TM 122) are needed for Michael reactions they may obyiously be made by the usual disconnection ... 

Analysis Start with the a,p-unsaturated relationship as the alternative (the 1,2-di O) is no good at the start. After the first disconnection we have a methyl ketone which can come from an acetylene ... 

Either 348A or B gives the right enamine, but B is an a,p-unsaturated ketone and so easier to disconnect. 

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 ... 

Analysis Another lactone FGl reveals the true TM (A). Our normal discormection a of an a,p-unsaturated carbonyl compound gives us the 1,5-dicarbonyl compound (B) and the ketone (C) clearly derived from phenol. Alternatively we could disconnect bond b to the keto-ester (D) with the further discormection shown ... 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

Antithetic conversion of a TGT by molecular rearrangement into a symmetrical precursor with the possibility for disconnection into two identical molecules. This case can be illustrated by the application of the Wittig rearrangement transform which converts 139 to 140 or the pinacol rearrangement transform which changes spiro ketone 141 into diol 142. 

Grignard addition to COg must be the answer with this crowded acid and this leads us back to alcohol (20), Disconnection of any group now gives a simple ketone and an available alkyl halide. As we shall see in Chapter 11, it is best to divide the molecule into two nearly equal parts, so we shall use disconnection (a). 

The synthesis of the natural product citronellol (1) (used in perfumery) shows guidelines 1 and 4 in action. Disconnection at the branchpoint is possible (la) and the required alcohol (2) comes from available ketone (3) (p Tl) by reduction. 

Ansuer Disconnection (a) on TM (8) gives symmetrical ketone (10). The alternative disconnection (b) would require bis-Grignard (11) - a doubtful species. 

Example As part of a programme to screen for new perfumery compounds, alcohol (17) was wanted. This has two branchpoints ( in 17) and disconnection between them simplifies the problem a great deal. Ketone (IS) is an available natural product (thujaketone) and halide (19) can be made via a Grignard reaction. 

Answer This branched primary amine can be made from ketone (21) via the oxime (p T 63). A 1,2 C-C disconnection on (21) is good as it needs the symmetrical allylic halide (22). 

Hence ketone (1) might be made by regioselective alkylation of (2) but this is doubtful. A safer route is to disconnect the ethyl group to leave nitrile (3) which can certainly be made by alkylation of nitrile (4) as there is only one site for enolisation. 

Optically active ketone (6) was needed for a study of asymmetric induction It could be made from acid (7) by a Friedel Crafts route or from nitrile (8) by Grignard addition, but neither of these compounds could be made by alkylation as the branchpoint is on the 3 carbon ( in each). The 1,3 C-C disconnection, e.g. (6b) is not good as it destroys the chiral centre. 

Compare these two routes to the simple ketone (33) and the one used on page T 130, Which disconnection and which synthons are used in each approach ... 

Frontalin (18), the pheromone of the western pine beetle, is an acetal (atom has two single bonds to oxygen). Disconnection reveals diol ketone (19). 

Answ r Two disconnections are possible for (1) giving either symnetrical ketone (3) or two molecules of the same ester (4),... 

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. 

Answer Ester disconnection gives a tertiary alcohol (4S), Of the three possible Grignard disconnections, (a) is most helpful as it requires the Mannich product (49) of an aryl ketone (50) available by the Friedel-Crafts reaction. 

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... 

Example Compound (27) was needed for synthesis of analogues of vernolepin, an anti-tumour compound. Robinson disconnection suggests unsymmetrical ketone (28)... 

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