Reagents-controlled cyclizations

To improve the utility of Nugent s and RajanBabu s conditions even further, catalytic conditions for cyclizations have been developed. They address the issue of reagent control of the cyclization and the mode of its termination. The formation of an alkyl titanocene species after reductive trapping allows two distinctive pathways for the regeneration of the catalyst. 

The spirocyclic acetal phyllanthocin (35) is the methyl ester of the aglycone of phyllanthoside, a compound of interest in the treatment of melanoma. McGuirk and Collum have completed a synthesis of optically active (35) which has as its key features the reaction of the lactone (31) with the novel chelated Grignard reagent (32) [leading to (33)] and the thermodynamically controlled cyclization of (33) to the spirocyclic acetal intermediate (34). 

The synthesis of 112 was then modified to provide a single enantiomer. This called for an asymmetric synthesis of cyclization substrate 111. This was accomplished by Midland reduction of ketone 113 to provide 114 with excellent enantioselectivity (Steroids-21). Alkylation of 114 with the appropriate bromide (prepared from 2-methylfuran according to the procedures described on Steroids-18), followed by a few well-precedented reactions, gave 115, and thence 111 and 112. Application of the Midland reduction is notable. This is a relatively early application of a reagent-controlled asymmetric synthesis. It is also notable that the Midland method works extremely well on alkyl alkynyl ketones (because they look like aldehydes to the reagent) and thus, is well-suited to this application. ... 

SCHEME 4.7 iiwrfo-cyclization through reagent control. 

Scheme 1.25 Reagent-controlled diastereoselective polyene cyclization of (S)-19 promoted by (R) or (S)-16.

The acyl residue controls the formation and stability of the carbonium ion. If the carbonium ion is destabilized (by electron withdrawing groups), then cyclization to the phenanthridine nucleus will be sluggish. The slower the rate of cyclization, the greater the chance of side reactions with the cyclization reagent. Therefore, the yield of the phenanthridine will depend on the relative rates of cyclization and side reactions, which is controlled by the stability of the carbonium ion. 

Manganese(III)-promoted radical cyclization of arylthioformanilides and a-benzoylthio-formanilides is a recently described microwave-assisted example for the synthesis of 2-arylbenzothiazoles and 2-benzoylbenzothiazoles. In this study, manganese triacetate is introduced as a new reagent to replace potassium ferricyanide or bromide. The 2-substituted benzothiazoles are generated in 6 min at 110°C imder microwave irradiation (300 W) in a domestic oven with no real control of the temperature (reflux of acetic acid) (Scheme 15). Conventional heating (oil bath) of the reaction at 110 °C for 6 h gave similar yields [16]. 

Most, perhaps all, of the reactions that simple alkenes undergo are also available to allenes. By virtue of their strain and of the small steric requirement of the sp-hybrid-ized carbon atom, the reactions of allenes usually take place more easily than the corresponding reactions of olefins. Because the allenes can also be chiral, they offer opportunities for control of the reaction products that are not available to simple alkenes. Finally, some reaction pathways are unique to allenes. For example, deprotonation of allenes with alkyllithium reagents to form allenyl anions is a facile process that has no counterpart in simple alkenes. These concepts will be illustrated by the discussion of cyclization reactions of allenes that follows. 

Several applications of this methodology are known. For the determination of the relative configuration of the stereocenter and the axial chiral unit of 71, the product of a diastereoselective ester enolate Claisen rearrangement of 70, with AgBF4 a cycli-zation to 72 was initiated. Then the carboxylic acid was reduced to alcohol 73 and the position of the substituents was investigated by NMR and by the use of NMR shift-reagents (Scheme 15.16) [32], Control experiments ensured the stereospecifi-city of the cyclization and the reduction step. There are further examples of this strategy [33]. 

The relation between the inter- and intramolecular acts is controlled by the reaction conditions such as type and concentration of the reagents, nature of the solvent, temperature, order in which the reagent are mixed, etc. This problem is discussed in much detail elsewhere 3). In this sub-section, we shall be only concerned with some of the experimental and theoretical studies aimed at revealing a relationship between the reagent structure and ineffective cyclization in the course of curing the epoxyamine compositions. 

Scheme 43 shows the details of the different steps involved in the equilibrium. The nucleophilic attack of the P(III) derivative on the acetylenic bond yields a 1,3-dipole which, after a fast protonation, frees aZ ion. If the subsequent addition of this ion occurs on the P atom (reaction a), a P(V) phosphorane is formed, but the addition of Z on the ethylenic C atom (reaction b) results in the formation of an ylide. Both of these reactions occur under kinetic control and, in both cases, X is always an OR group from the initial acetylene dicarboxylic ester. When the acetylenic compound is a diketone and X is an alkyl or aryl moiety, the C=0 group is much more electrophilic and the attack by the Z ion produces an alcoholate (reaction c), a new intermediate which can cyclize on to the P+ to form a phosphorane, or attack the a-C atom to form an ylide as in Scheme 42. Hence, reactions a and c can coexist, and are strongly dependent on the nature of the trapping reagent and of the P compound, but reaction b is blocked, whatever the reagent. This is well illustrated by the reaction of the 2-methoxytetramethylphospholane 147 on diben-zoylacetylene in the presence of methanol as trapping reagent. The proportions of the vinylphosphorane 157 and spirophosphorane 158 formed (Figure 24) are 13% and 84%, respectively.

The regioselectivity in the cyclization process of unsymmetrical adducts is controlled by the ability of the ortho substituent to accommodate the developing negative charge in the transition state.128 However, the observed orientation of the reagent may also depend on other factors and still is not well understood. 

A mixture of methanesulfonic acid and P2Os used either neat or diluted with sulfolane or CH2C12 is a strongly acidic system. It has been used to control the rcgiosclcctivity in cyclization of unsymmetrical ketones. Use of the neat reagent favours reaction into the less substituted branch whereas diluted solutions favour the more substituted branch[3]. 

The acetonation under kinetically controlled conditions is also useful for the protection of vicinal rra/u-diols, which are quite reluctant to cyclization into five-membered rings. Although use of 2-methoxypropene has been successful in this objective [61,66], one should recommend the recently discovered uses of reagents that minimized the ring strain by obtaining six-membered rings from vicinal mmr-dials, which are protected (Scheme 10) as 1,4-dioxanes (dispiroacetals, rranr-decalinic system) stabilized by an anomeric effect... 

---