Aldol transannular

In a recent total synthesis of the novel neurotrophic agent merrilactone A (22, Scheme 4) by Inoue and Hirama [24], key intermediate 21 with the cis-bicyclo[3.3.0] octane framework embedded within the caged pentacycle 22 was elaborated from cyclobutane 18 by a sequence of RCM and immediate cleavage of the resulting bicyclic vicinal diol 19 to raeso-diketone 20. Cyclooctenedione 20 then underwent regioselective transannular aldol reaction at low temperature (LHMDS, THF, -100 °C) to produce a 3 1 mixture of isomers in 85% combined yield. The major isomer 21 with the required stereochemistry was then converted into the racemic natural compound ( )-22 in 19 steps. 

Scheme 4 A sequence of RCM-glycol cleavage-transannular aldol reaction in Inoue s total synthesis of merrilactone A (22) [24]...

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

This model is extremely useful in understanding the stereochemical outcomes of aldol processes. It also provides a framework for influencing the diastereose-lectivity in a rational way. For instance, if the ethoxy group in the above example is changed to a much bulkier group, increased transannular interactions in the pseudoaxial transition state would make it even higher in energy and result in increased selectivity for the anti isomer (and it does )... 

The transformation of VIII/3 to VIII/4 is called a fragmentation1 [3] [4]. As in the aldol reaction the reverse version of the fragmentation also is known (VIII/4 — VIII/3). An example of this reaction type is the so-called Prins reaction the acid catalyzed (base catalysis is also possible) addition of an olefin to formaldehyde in order to get a 1,3-diol. Further examples are known in the field of transannular reactions in medium-sized rings [5],... 

In the case of synthetic studies on mitomycins (e.g. mitomycin A), both techniques were applied to synthesize model compounds. A retro aldol reaction, followed by a trivial transannular reaction, was performed in the same pot and under the same conditions (sodium hydride) [79] [80], Scheme VIII/25. Thus, compound VIII/132 gave the ring closed intermediate, VIII/133, which by a retro aldol reaction, yielded the eight-membered intermediate, VIII/134. A transannular reaction in VIII/134 gave the acid labile VIII/135, which led finally to the indole derivative, VIII/136. 

In an alternative approach to molecules of this type, Dauben and Hart examined the base-catalyzed rearrangement of vinylogous 0-hydroxy ketones such as 305 and 308 (Scheme 48).321 Their conversion to 306 and 309 can be accounted for in terms of a vinylogous retro-aldol condensation followed by intramolecular 1,4 addition of an intermediate dienolate to the resulting enone moiety. Subsequent to this reaction, conjugation of the double bond away from the ring juncture followed by a transannular vinylogous aldol condensation produces the observed products. 

Chiral phosphoramides, particularly C2-symmetric examples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been reported. A number of chiral, non-racemic cyclic phosphoramide receptors (387) have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found. Evidence from a combination of its X-ray structure, NMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state. A series of isomers of l,3,2-oxazaphosphorino[4,3-a]isoquinolines(389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by H, C, and P NMR spectroscopy and X-ray crystallography... 

In fact, diketones in a medium sized ring give several transannular reactions such as pinacol coupling [equation (i)] or aldolization [equation The later reaction also occurs during hydrogenation of aliphatic monoketones under favorable conditions (Pd-on-carbon, zeolite, 200°C, 4 X 10 kPa) to produce methyl isobutyl ketone from acetone (in 96%) -... 

Macrocyclic diketones can undergo transannular aldol cyclization reactions, giving bicyclic aldols. A representative example is seen in the cyclization of 1,6-cyclodecanedione to the corresponding hy-droazulenone (equation 142). Aldolization of the related cyclodecadienedione (120) has also been examined under mildly basic conditions aldols (121) and (122) are the main products, being formed in a ratio of 1 4 (equation 143). Control experiments with the pure aldols showed that this is the thermodynamic ratio of isomers. 

Proline is effective in mediating an asymmetric transannular aldol reaction." ... 

If a carbonyl group is attached a to position 1 of the pericyclic system, the oxy-Cope rearrangement of divinylcyclohexanes results in the formation of medium ring enolates, which after proton transfer undergo a transannular vinylogeous aldol-type reaction (probably a transannu-lar, intramolecular Michael-type reaction). For example, tricyclic alcohol 4 is obtained via such a reaction sequence from 1 in 45% yield1129. 

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