Page 162 - Advanced Organic Chemistry Part B - Reactions & Synthesis

134 hexacoordinate. If the reactants are chiral, facial selectivity must be taken into account.
Examples of steric, chelation, and polar effects on TS structure have been described.
CHAPTER 2 Chiral auxiliaries can influence facial selectivity not only by their inherent steric effects,
Reactions of Carbon but also on the basis of the conformation of their Lewis acid complexes. This can be
Nucleophiles with
Carbonyl Compounds controlled by the choice of the enolate metal and reaction conditions. Dialkylboron
enolates react through a cyclic TS that cannot accommodate additional coordination.
Titanium and tin enolates of oxazolidinones are chelated under normal conditions, but
the use of excess Lewis acid can modify the TS structure and reverse facial selectivity.
Chiral catalysts require that additional stereochemical features be taken into account,
and the issue becomes the fit of the reactants within the chiral environment. Although
most catalysts rely primarily on steric factors for facial selectivity, hydrogen bonding
and stacking can also come into play.

2.1.6. Intramolecular Aldol Reactions and the Robinson Annulation

The aldol reaction can be applied to dicarbonyl compounds in which the
two groups are favorably disposed for intramolecular reaction. Kinetic studies on
cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that
formation of five-membered rings is thermodynamically somewhat more favorable
than formation of six-membered rings, but that the latter is several thousand times
faster. 170 A catalytic amount of acid or base is frequently satisfactory for formation
of five- and six-membered rings, but with more complex structures, the techniques
required for directed aldol condensations are used.
Scheme 2.10 illustrates intramolecular aldol condensations. Entries 1 and 2
are cases of formation of five-membered rings, with aldehyde groups serving as
the electrophilic center. The regioselectivity in Entry 1 is due to the potential for
dehydration of only one of the cyclic aldol adducts.
OH CH O CH O
CH O
O CH
CH O OH CH(CH )
)
CH(CH 3 2 3 2
CH(CH ) CH(CH )
3 2 3 2
dehydration not
available
In Entry 2, the more reactive aldehyde group serves as the electrophilic component
in preference to the ketone. Entries 3 to 6 are examples of construction of new rings
in preexisting cyclic systems. The structure and stereochemistry of the products of
these reactions are dictated by ring geometry and the proximity of reactive groups.
Entry 5 is interesting in that it results in the formation of a bridgehead double bond.
Entries 7 to 9 are intramolecular Mukaiyama reactions, using acetals as the precursor
of the electrophilic center. Entry 9, which is a key step in the synthesis of jatrophones,
involves formation of an eleven-membered ring. From a retrosynthetic perspective,
bonds between a carbinol (or equivalent) carbon and a carbon that is to a carbonyl
carbon are candidates for formation by intramolecular aldol additions.
A particularly important example of the intramolecular aldol reaction is the
Robinson annulation, a procedure that constructs a new six-membered ring from a
ketone. 171 The reaction sequence starts with conjugate addition of the enolate to methyl

170
J. P. Guthrie and J. Guo, J. Am. Chem. Soc., 118, 11472 (1996).