Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
(O-allylendo3), Miranda and co-workers 183 found that the “anti-
Michael” 5-(O-allylendo3)-exo-dig product is formed in 79% yield
when using a protic solvent (EtOH). However, in acetone, the
major product derives from the formal 6-(O-allylendo3)-endodig
closure. These observations suggest that the 5-exo cyclization
is kinetically favorable and gives the product as long as the
cyclized carbanion is quickly and irreversibly trapped by protonation.
In an aprotic solvent, the initially formed 5-exo-dig vinyl anion
has enough time to rearrange to the more stable 6-endo-dig product,
as has been suggested in similar systems (Scheme 55). 184,56 Tietze
and co-workers have used this strategy for six-membered ring
formation in their syntheses of several anthrapyran natural
products. 185
Scheme 55. Solvent-Dependent Cyclizations of Oxygen
Anions with Three sp 2 -Atoms in the Linking Chain
A formal 6-(O-allylendo2)-endo-dig cyclization has been
reported by Padwa et al. (Scheme 56). 186 However, the authors
do not exclude the initial formation of a 5-exo product which
could rearrange in the six-membered benzopyran ring under
workup conditions, similar to an analogous rearrangement
reported by them for similar benzylic alcohols (vide infra,
Scheme 57).
Scheme 56. Formal O-6-(enolendo)-endo Cyclization
Closure onto Aryl-Substituted Alkynes
Cyclizations of other oxygen nucleophiles corresponding to
motif A are also common. As expected based on the above calculations
(Table 23), base-catalyzed cyclizations of aliphatic alcohols
exclusively follow the 5-exo path, the vinyl anion serving as the base
for another acyclic alcohol. When a secondary allylic alcohol 187 is
used as opposed to a primary alcohol, 188 gem-dimethyl groups are
required to facilitate the regioselective transformation. Trost and
Runge found that reactions of secondary allylic alcohols with electron
deficient alkynes were inefficient(