4-Methyl-2-cycloheptenone

The addition of lithium dipropylcuprate-boron trifluoride to 4-methyl-2-cycloheptenone produced a d.r. (trans/cis) of 83 17, and almost the same degree of diastereoselectivity was obtained in the case of 5-methyl-2-cycloheptenone23. However, 6-methyl-2-cycloheptenone gave a d.r. (trans/cis) ratio of 37 6323. 

It is gratifying that the same model holds for the conformationally more flexible cyclohep-tenones. Again, the 4-methyl-2-cycloheptenone led preferentially to the s-compound in the (2-propenyl)siIane addition, based on stereoelectronic grounds. 

Similarly, the [3-1-4] annulation of the E- and Z-isomers of /3-hetero-substituted acryloylsilanes 52 with lithium enolates of a,-unsaturated methyl ketones 54 gave stereospecifically the c -6,7-cyclopentyl-5-trimethylsilyl-3-cycloheptenone 55 (equation 20). The stereospecificity in the annulation was explained by an anionic oxy-Cope isomerization of the 1,2-divinylcyclopropanediol intermediate 56, which was generated through the Brook isomerization of the initial 1,2-adduct (equation 20). 

Dihydrofuran undergoes a thermal rearrangement to cyclopropanecarbaldehyde, and 5-methyl-2,3-dihydrofuran similarly affords acetylcyclopropane. 2,5-Dimethyl-2-vinyl-2,3-dihydrofuran undergoes thermal rearrangement to 4-methyl-4-cycloheptenone (66JA4294). 

The cyclization can be extended to preparation of 3-methyl-2-cyclohexenones and 3-methyl-2-cycloheptenones, but yields are low. 

CYCLOHEPTENONES 3-Bromo-3-methyl-2-trimethylsiloxy-I-butene. Lithium phcnylthiol 2-vinylcyclopropyl)-cuprate. 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

Of these two options, the second has a possible problem of regioselectivity during the rearrangement, as shown in the Fig. 9. As we have shown [30], this regioselectivity is determined by migratory aptitudes and can be exclusive, as presented below (Fig. 10). We have also investigated the cyclopropanation/ intercyclic bond cleavage of simple monoterpenes as an easy access to enan-tiopure 1,4-methyl-isopropyl substituted cycloheptenones, as shown also in Fig. 10 [31-33]. 

The dihydrofuran A gives 4-methyl-4-cycloheptenone on heating in the range 140-200 . Account for this transformation. 

Cycloadditions of dienes e.g. isoprene) with 3-halogeno-3-methyl-2-trimethylsilyloxybut-l-enes in the presence of silver perchlorate or zinc chloride ° give cycloheptenones in moderate yield. 

In a further demonstration of the preparative potential of this chemistry, multigram quantities of four-membered carbocycles were investigated (Scheme 4.6) [24,26]. The reaction of 22.0 mmol of silyl enol ether with methyl acrylate gave the desired cyclobutane 2 a in 90% yield. Furthermore, multigram quantities of four-membered carbocycles were obtained from cycloheptenone in two steps, without purification of the intermediate silyl enol ether. These two-step sequences, using methyl acrylate and ethyl propiolate, led to large-scale production of the respective bicyclic cyclobutane 20d and cyclobutene 22c, in excellent overall yields. 

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