Cyclization general problems

The construction of enantiomerically-pure carbocycles is a general problem in organic synthesis. Dirk Trauner (UC Berkeley) reports (Organic Lett. 2003, 5,4113-4115) an elegant intramolecular Heck cyclization. The alcohol 7 is readily prepared in enantiomerically-pure form. Conditions can be varied so that either 8 or 9 is the dominant product from the cyclization. 

The general problem of lack of selectivity in the lactonization step was dealt with in subsequent studies by Winterfeldt, as outlined in Scheme l.S ." Compound 224 was desilylated to afford a mixture of diastereomeric secondary alcohols 228a and 228b. Esterification of these alcohols with dimethylphosphorylacetic acid then gave the cyclization precursors 229a and 229b. Deprotonation and subsequent phophonate condensation unfortunately led to a stereoselective cyclization of the undesired diastereomer. Thus isolation... 

A study of the photochemical Cope reaction of the hexadienes 40 has been carried out under photoinduced electron-transfer conditions. Evidence was gathered for the formation of a chair cyclohexane-1,4-radical cation 41 °. In snch systems, where the radical cation is formed using DCA as the sensitizer, a degenerate Cope process is operative. Thus when the tetradeuterio derivative 42 is used, rearrangement affords a (52 48) mixture of the two dienes 42 and 43. Related to this general problem, DCA-sensitized reactions of the isomeric dienes 44 and , -45 and the cyclization prodnct, the bicyclohexane 46, have been studied in considerable detail. At low conversions, the irradiation of 46 affords a mixture of the dienes 44 and , -45 in ratios that are independent of temperature. The influence of the position of the aiyl groups on the diene skeleton has also been studied. This does not appear to affect the conversion to a cyclic radical cation. Thus the SET-induced reaction of the diene 47 has shown that the open chain radical cation of the diene 48 cyclizes preferentially to the radical cation 49. ... 

The oxindole construction mentioned above is a variation of an oxindole synthesis developed by Jones. An application of this method to the synthesis of horsfi-line is outlined in Eq. (11) [21], It is notable that whereas the cyclization of 37 is quite efficient, attempts to cyclize amide 38 gave only reduction of the aryl bromide. This is a common problem in radical cyclizations involving secondary amides as the ii-geometry of the amide precludes cyclization. This general problem was first... 

Mn(in)-mediated electrochemical oxidative cyclization was successful in some cases, such as that of 4, which gives up to 59% of 8 with only 10% of the theoretical amount of Mn(III). However, the electrochemical cyclizations generally give lower yields than the stoichiometric Mn(III) oxidative cyclizations, and more complex product mixtures are typically obtained. One problem is that Mn(III) oxidations are relatively slow at room temperature. Therefore elevated temperatures must be used in the electrochemical cyclizations. This can lead to further oxidation as in the formation of 18 and 19 from 9 by oxidation of the initial product 14. It is hard to determine why the yields are lower in other cases since we were unable to isolate byproducts. We can only speculate that either the starting materials or the products are oxidized at the electrode to give polymeric material. NaI04 in DMSO can be used to chemically reoxidize Mn(II) to Mn(III). Under these conditions 4 affords 60% of 8 with only 5% of the theoretical amount of Mn(III). 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

More promising from a synthetic point of view are the reactions of nitrenium ions that are covalently linked to aromatic substrates. The constraints provided by the linker generally reduce or eliminate the problem of forming multiple regio-isomers. Wardrop et applied the cyclization of acylalkoxynitrenium ions... 

C-2 Chain extension via allylation (578->579) followed by oxidation to expose a latent aldehyde and cyclization constitutes another general route, in this case, leading to skimmianine (580) (Scheme 174) [73JCS(P1)94]. These routes, which overcome problems of poor 3-position reactivity by electrophilic substitution chemistry, were also applied to the furoquinoline... 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

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