Cyclohexanone Ring Construction

Possible schemes that would satisfy the plus-minus combinations are given in the following. Option A 

Looking at these options it appears that two-bond disconnection possibilities are the most attractive. In particular, options A, C, F, H, and I are elegant solutions to the problem and appear to be practical with the least complications from competing side reactions. However, the ultimate test of validity is actually doing the experiment and finding out the results. Many a chemist has been humbled or exhilarated by the outcome as the case may be. 

In summary, the following steps help to streamline retrosynthetic analysis toward direct and efficient synthetic routes, especially for ring construction  

Identify symmetry elanents in the final target structure. 

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Intramolecular carbene insertion (e.g. 1 —> 3) has long been a useful method for ring construction. Masahisa Nakada of Waseda University in Tokyo now reports (J. Am. Chem. Soc. 125 2860, 2003) that with the addition of the ligand 2 this process can be made highly enantioselective. As the starting diazo ketone 1 is easily prepared by diazo transfer to the sulfonyl ketone, this should allow facile entry to enantioenriched cyclopentanones and cyclohexanones. 

One of the most powerful strategies for asymmetric ring construction is to desymmelrize a preformed ring. Yasamusa Hamada of Chiba University in Japan has reported (J. Am. Chem. Soc. 2004, /26, 3690) that the inexpensive diaminophosphine oxide 2 nicely catalyzes the asymmetric alkylation of the cyclohexanone carboxylate 1 to give 3. Although no examples were given, this asymmetric alkylation would probably work as well with heterocyclic P-ketoesters. 

When an oc,/)-unsaturated ketone is the acceptor, subsequent ring closure to yield a six-membered ring can occur, in two modes. As shown in Scheme 3, the initially formed enolate oxygen can add to the immonium ion of the dipolar intermediate to generate a dihydropyran (e.g., 3.2, Y = 0, X = C). Alternatively, proton transfer from the initially formed enolate and subsequent carbon-carbon bond construction between the enolate and the immonium ion can produce a new cyclohexanone ring. Elimination of the amine usually ensues to generate the corresponding cyclohexenone. This amine-promoted Robinson annelation is commonly referred to as a Stork annelation (3, 22). 

Appropriate application of connectivity analysis especially for ring constructions can go a long way in coming up with direct synthetic routes to such targets as was done in the cyclohexanone example given in Section 9.1.3. 

With cyclic a-halo ketones, e.g. 2-chloro cyclohexanone 6, the Favorskii rearrangement leads to a ring contraction by one carbon atom. This type of reaction has for example found application as a key step in the synthesis of cubane by Eaton and Cole for the construction of the cubic carbon skeleton ... 

The vinylbenzothiazoles can also function as very efficient Michael acceptors (78TL13). The a-lithio derivative of acetone dimethylhydrazone undergoes clean conjugate addition to the vinylbenzothiazole derived from cyclohexanone to provide, upon quenching the a-lithiobenzothiazole anion with methyl iodide and hydrolyzing the dimethylhydrazone group, the ketone (579) (93% overall, 86 14 cis trans). The pure cis keto benzothiazole was converted to the cis keto aldehyde (580), and then cyclized with p-toluenesulfonic acid to the A -3-octalone (581 Scheme 127). Many other examples of the use of this chemistry for the construction of fused and spiro ring systems have been developed. 

The very high nucleophilicity of a-heterosubstituted a-lithiocyclopropanes and of a-lithioalkyl selenides, even those bearing two alkyl groups on the, carbanionic center, permits the stepwise construction of a cyclopentane ring possessing several quaternary centers in vicinal positions with respect to one another by two successive ring expansion reactions from a suitably functionalyzed cyclopropane 135,224) (Schemes 98, 101). This feature has been used by Fitjer2240 for the synthesis of permethyl cyclobutanone, permethyl cyclopentanone, and even permethyl cyclohexanone, as well as for the preparation of previously unknown permethylcyclohexane. 

A fruitful method for formation of 3-substituted cyclohexanones 26 utilizes a one-carbon ring-expansion process starting from 2-substituted cyclopentanones 23. A bromomethyl, iodo-methyl, or phenylselanylmethyl group is introduced at C2 in the jS-position by base-catalyzed alkylation. Treatment of the resulting 2,2-difunctionalized cyclopentanone 24 with tributyltin hydride generates a bicyclo[3.1.0]hexan-l-oxyl radical 25 as a transient intermediate which rearranges and abstracts hydrogen to construct the 3-substituted cyclohexanone 26. 

The second key step is lactone formation from the carboethoxy substituted cyclohexanone unit in 44. The third key step is construction of the tricyclic ring system by asymmetric radical cyclization of 43, and construction of 43 from 2-isopropylphenol (42) using alcohol chiral auxiliaries (R OH) was designated as the fourth key step. This disconnection scheme represents Yang s specific approach using key chemical transformations such as radical cyclization (see sec. 13.7). Clearly, other disconnections are possible, and at each stage other disconnections could lead to alternate synthetic trees. 

Ethoxyallylidenetriphenylphosphorane (94) has been shown to be a novel cyclohexanone annelating reagent, undergoing addition to a/8-unsaturated ketones to produce 2-alkoxycyclohexa-1,3-dienes (masked cyclohexenones and useful eno-philes) (Scheme 24)7 The method is highly versatile, permitting the construction of monocyclic, fused, bicyclic, and spiro-ring systems. 

Overman and coworkers synthesized the ABC core (177) by a stereoselective intramolecular Maimich reaction from tra s-2,3-dialkylated cyclohexanone (180), which was prepared from D-(-)-quinic acid [95] (Scheme 15). The ABC ring system was constructed by ene-amide formation. The ene-amide (178) was converted to 177 by successive epoxidation, add-rearrangement, and ehmination. 

The intramolecular variant of ester condensation is known as the Dieckmann reaction and preferred for construction of thermodynamically favored medium rings without steric strain, in particular cyclopentanone and cyclohexanone derivatives. 

All of these disconnections describe annulation (annelation) routes to cyclohexanone derivatives. There are tactical issues involved with executing the strategies in the lab that we will not discuss here. Of course these are not the only ways to construct simple cyclohexanone derivatives. The problems explore several other approaches. Nonetheless these are versatile strategies that have been widely used in organic synthesis. One point to take away from this exercise is that 6-membered rings can be prepared without resorting to use of A-functions. Although we have seen this only for carbocycles, it turns out this is true for heterocycles as well (see the problems). 

The synthesis of NH- and N-vinyl-4,5,6,7-tetrahydroindoles is implanented successfully at cyclohexanone oxime-acetylene molar ratio of l (2-5) at 90 C-140 C. At temperature below 90°C, the reaction proceeds slowly, and the rate of side processes increases above 140°C. The bases (alkali metal hydroxides and alcoholates) taken in 10%-50% amounts relative to cyclohexanone oxime serve as the reaction catalysts. The reaction is efficiently catalyzed by potassium, rubidium, and tetrabutylammonium hydroxides. It should be noted that the last two bases have a selective effect on the construction of the tetrahydroindole ring (synthesis of... 

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