Baldwin's Rules - Department of Medicinal Chemistry

Chemical Reviews REVIEW
Table 24. Transition State Geometries, NICS (0) Values, and
LUMO Plots for 5-exo/6-endo Carbanionic Cyclizations for
the Me-Substituted Alkyne Calculated at the M05-2X/
6-31+G** Level c
a Energies are given relative to the near-attack conformations
(NAC). The anti-anti conformation is ∼4 5 kcal/mol stable than
the NACs. b This cyclization is barrierless. c Bond lengths given in Å.
Activation, reaction, and intrinsic energies (kcal/mol) for the
parent 5-exo- and 6-endo-dig anionic cyclizations at the B3LYP/
6-31+G(d,p) and M05-2X/6-31+G(d,p) levels of theory. M05-2X
data are given in parentheses and the ring-closing bonds are shown
in red.
Scheme 46. sp 3 -Anionic 5-exo-dig Closures with Completely
Saturated Linkers
The regioselectivity of alkyl lithium reagents for TMSsubstituted
alkynes is unaffected by two sp 2 carboninthe
bridge, affording the 5-exo-dig closure in excellent yields
(94 100%, Scheme 47). 172b
Scheme 47. sp 3 -Nucleophiles with Two sp 2 Centers in the
Chain Linking the Nucleophile with the Alkyne
Although the analogous cyclizations of σ-vinylexo anions
(motif B) are still fully 5-exo-dig selective, the reactions are
much slower (sp 2 -hybridized carbanions are less reactive) and
simple alkyl substituted alkynes mostly give the products resulting
from intermolecular capture of the intermediate acyclic
vinyl anion (Scheme 48). This limitation notwithstanding, the
cyclizations of aryl or silylated alkynes proceed smoothly
(83 94%). 172b,174
Scheme 48. Nucleophilic 5-(σ-Vinylexo)-exo-dig Ring
Closure of Vinyl Lithiums
Negishi and co-workers have shown that simple σ-vinylendo
anions (motif C) also undergo selective 5-exo-dig cyclizations 172b
(Scheme 49). Later, Myers and co-workers have utilized such
regioselective closure of reactive species formed via Br Li
exchange at an endocyclic vinyl bromide adjacent to an ethynyl
moiety in the development of synthetic approaches toward
Kedarcidin and related natural products. These examples of
5-(σ-vinylendo)-exo-dig cyclizations gave the desired product in
up to 52% (Scheme 49) 175 At the reported experimental conditions
( 78 °C in THF), this reaction is believed to proceed
through a carbanionic pathway. 172b,176
Scheme 49. Regioselective 5-(σ-Vinylendo)-exodig
Cyclizations
Using a thiazole bridge, Arcadi et al. have proposed that an
imine intermediate is what undergoes a 6-(σ-vinylendo)-endo-dig
cyclization onto aromatic- and aliphatic-substituted alkynes in
74 95% yields (Scheme 50). 177 Wu and co-workers found that
when an iminyl anion is attached to a benzene ring, the
regioselectivity can be tuned based on the nature of the alkynyl
AC dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000