Internal alkylation synthesis

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

Vedejs developed an enantiocontrolled synthesis of aziridinomitosenes involving internal alkylation of the oxazole 132 to produce an oxazolium salt 133 followed by nucleophilic addition of cyanide providing the adduct 134 <00JA5401>. Electrocyclic ring opening of 134 to the azomethine ylide 135 with internal [2+3] trapping produces the tetracyclic product 137 via the pyrroline 136. 

Cyano-stabilized anions have been internally alkylated to generate 10-581, 14-582 and 16-membered583-586 rings. The ring-closure step in a synthesis of zearalenone has been performed in this way (equation 89)582. 

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

Internal alkylation takes place on reaction of a-haloalkyl alkyl sulfones with bases and produces epi-sulfones as intermediaries. These intermediates are usually unstable and provide alkenes by thermal extrusion of sulfur dioxide. This reaction, known as the Ramberg-Backlund rearrangement, has been widely used in synthesis and has been thoroughly reviewed (Scheme 107, entry e).36-3. 43<.473... 

In a second variation, one molar equivalent of sodiomalonic ester is allowed to react with one molar equivalent of a dihaloalkane. This reaction gives a haloalkylmalonic ester, which, when treated with sodium ethoxide, undergoes an internal alkylation reaction. This method has been used to prepare three-, four-, five-, and six-membered rings. An example is the synthesis of cyclobutanecarboxylic acid ... 

Natural Products,—A minor component of the essential oil from Geranium macror-rhizum L. leaves has been identified as the novel sesquiterpene ketone germazone (721). A stereospecific synthesis of (722), an intermediate in the preparation of isoclovene, has been reported. The key steps in a reported total synthesis of ( + )-cis-sativenediol (726) involve internal alkylation to the cyclopropane derivative... 

An enantioselective total synthesis of (+)-phomactin A (181) has been recently reported by Halcomb using intramolecular Suzuki coupling of a B-alkyl-9-BBN derivative to prepare the macrocycle in the final step [162,163], Thus, a regioselective hydroboration of the terminal olefin in the precursor 182 gave an internal alkyl-borane that was cyclized using modification of Johnson s conditions [164], The reaction illustrates the mildness of the Suzuki reaction since the coupling was carried out in the presence of the sensitive dihydrofuran ring (Scheme 3.95). 

A related enamine alkylation is seen in the rearrangement of an ethylene imine vinylogous amide, which was heated with sodium iodide in diglyme. The presumed internal enamine alkylation constitutes a critical step in an oxocrinane synthesis (265). Use of an ethylene imine urethane for alkylation of an enamine and formation of the hexahydroindole system has also been reported (266). 

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