Ketones seven-membered ring synthesis

Preparation of spirooxaziridines from cyclic ketones poses no problems nor does oxaziridine synthesis from cyclic Schiff bases, which was preferably carried out with pyrro-lines to give, for example (245) (59JCS2102) and, in connection with tranquilizer synthesis, with heterocyclic seven-membered rings to give, for example, (246) (63JOC2459). 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

The enthalpy of fomation of two such species has been measured, namely the cyclopropane and cycloheptane derivatives. The difference between the values for these two species, both as solids, is 238.1 kJmol . Is this difference plausible Consider the difference between the enthalpies of formation of the parent cycloalkanes as solids, 194 kJ mol . The ca 44 kJ mol discrepancy between these two differences seems rather large. However, there are idiosyncracies associated with the enthalpies of formation of compounds with three-membered rings and almost nothing is known at all about the thermochemistry of compounds with seven-membered rings. Rather, we merely note that a seemingly well-defined synthesis of cycloheptyl methyl ketone was shown later to result in a mixture of methyl methylcyclohexyl ketones, and superelectrophilic carbonylation of cycloheptane resulted in the same products as methylcyclohexane, namely esters of 1-methylcyclohexanecarboxylic acid. The difference between the enthalpies of formation of the unsubstituted alicyclic hydrocarbons cycloheptane and methylcyclohexane as solids is 33 kJmol . This alternative structural assignment hereby corrects for most of the above 44 kJ mol discrepancy in the enthalpies of formation of the two oximes. More thermochemical measurements are needed, of oximes and cycloheptanes alike. 

The synthesis of 1,4-thiazepines from chalcones 184 is also possible on solid support. This has been shown by Lee etal. In an one-step bis-nucleophilic attack of 75, loaded on Wang or Rink amide resin, to the a,[)-unsaturated ketone 184, the seven-membered ring 192 is formed. TFA cleavage afforded more than 29% overall yield (Equation 14) <2001TL109>. 

However, we are not surprised that an enolate ion is formed from a ketone in basic solution. The oxyallyl cation is much more surprising. How can we be convinced that it really is an intermediate There are several alternative ways to make the same intermediate. If basic nucleophiles such as the methoxide ion are avoided and reaction of zinc with an a,a -dibromoketone in a nonnucleophilic solvent like diglyme is used instead, the oxyallyl cation can be trapped in a Diels-Alder reaction. This is tile basis for a good synthesis of seven-membered rings. 

This is a LiAlH4 reduction of the a,(3-unsaturated ketone of the seven-membered ring. The low temperature and the use of only 0.25 eq. of LiAlH4 ensures that only the fastest reaction takes place and no reduction of the ketone in the five-membered ring or of the double bonds is observed. This reduction proceeds with substrate control of the diastereoselectivity, because the hydride attacks the molecule mainly from its convex and not from its concave face. This becomes clear when looking at 44 which is a three-dimensional representation of 31. Whether the diastereomeric ratio of 10 1 is important, will become clear in the further synthesis. 

The total synthesis of the diterpenoid tropone, harringtonolide was accomplished in the laboratory of L.N. Mander. The key step to form the seven-membered ring was the Buchner reaction of a complex polycyclic diazo ketone intermediate. Upon treatment with rhodium mandelate, an unstable adduct was formed and was immediately treated with DBU to afford the less labile cycloheptatriene. 

The synthesis of cyclic ketones via acyl radical cyclizations represent by far the most frequently investigated approaches in the past two decades and such cyclizations are well discussed in a recent review [la]. Two recent examples of the application to natural product synthesis are given here. A seven-membered ring, a key compound in the overall synthesis of (-i-)-confertin, was prepared by Shishido and co-workers, utilizing 1-endo-trig acyl radical cyclization which occurred in a highly efficient manner (Scheme 4-39) [66]. 

Corey and Nozoe cyclized a keto aldehyde as one step in a total synthesis of helminthosphoral (equation 106). In this case, note that the aldehyde enolate adds to the more hindered ketone carbonyl to form a five-membered ring. The alternative addition of the ketone enolate to the aldehyde would give a seven-membered ring. 

Under strictly anhydrous conditions, the iminophosphorane intermediate that is formed as a result of the Staudinger reaction can react with aldehydes and ketones in an intermolecular fashion (as in the synthesis of imine 36 described above) or intramolecularly with a variety of carbonyl containing functional groups to afford a host of products. Nitrogen containing ring systems such as cyclic imines (44) represent just one of the many products one can prepare and the reaction is particularly well suited for the facile synthesis of five, six, and seven-membered rings. In addition to aldehydes and ketones, carboxylic acids, esters, thio-esters, and amides can also react in an intramolecular fashion to trap an iminophosphorane to afford a variety of heterocycles. Examples from the current literature are described in Section 2.5.5. 

Treatment of crude akynylalkanols (92), which are obtainable from (91) and 1-alkynylmagnesium halides, with hot aqueous acid provides a convenient synthesis of 3,5-di- and 2,3,5-trisubstituted (five-, six-, and seven-membered ring-fused) thiophenes (93) (Scheme 25) <89S2io>. Starting materials (91) are easily synthesized from a-halo ketones in high yields. The reaction may involve electrophilic attack of vinyl cation, produced by protonation of the triple bond, on the sulfur. 

---